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Human herpesvirus 6 (HHV-6) is associated with its presentation in the pediatric population as roseola infantum. Rarely, it is the causative agent of encephalitis, with most cases reported among the immunocompromised population due to reactivation. This review article analyzes the published records of cases labeled HHV-6 encephalitis in immunocompetent adults, aiming to understand the diagnostic methods behind each case and explore the complexities of such a diagnosis. We note significant variability in the methods used to come to a diagnosis of HHV-6 encephalitis, as well as inconsistent approaches to treatment of this condition. Given the rarity of HHV-6 encephalitis in immunocompetent adults, there are no clearly structured diagnostic guidelines for this condition in this patient population. We highlight several diagnostic methods that provide more convincing evidence of true HHV-6 encephalitis and may provide a basis for further development of guidelines for the diagnosis and treatment of this condition. [ABSTRACT FROM AUTHOR]

Purpose: to propose a step­by­step treatment regimen for betaherpetic keratitis with a method for monitoring the dynamics of the disease.Patients and methods. The study group included 40 patients (40 eyes). Each patient had a history of diagnosed unilateral recurrent acute or subacute keratitis, the etiology of the betaherpetic process was confirmed by laboratory diagnostic methods, confocal microscopy, based on the detection of specific “owl eye” cells. All subjects had previously received specific therapy with acyclovir. All patients underwent an ophthalmological examination, and then a two­stage treatment regimen for keratitis was proposed. The main way to assess the dynamics of the disease, the presence of viral load and the need to intensify antiviral therapy was confocal microscopy data. The condition was assessed 1, 3, 6 and 12 months after the start of therapy. Results. As a result of the observation of a group of patients of 40 people, after 12 months, 33 patients achieved stable remission, 4 patients developed neurotrophic keratitis, and 3 patients had a relapse of betaherpetic keratitis. Recurrence of keratitis in 3 patients was detected within 2 to 4 months from the start of observation. Neurotrophic keratitis developed in 4 patients within 3 to 6 months from the start of observation.Conclusion. 1) The method of in vivo confocal microscopy can be used to monitor the dynamics of betaherpetic keratitis, based on the state of specific cells. 2) Therapy of betaherpetic keratitis requires the use of specific antiviral drugs with mandatory repeated preventive courses. 3) A history of herpesvirus infection requires assessment of the development of neurotrophic keratitis.

Background: Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders. Objective: The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up. Methods: A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed. Results: A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0). Conclusion: MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results. [ABSTRACT FROM AUTHOR]

Leukocytosis in neonates can occur because of infectious, inflammatory, malignant, or physiological processes. Hyperleukocytosis is defined as a total leukocyte count (TLC) exceeding 100,000 per mm3, warranting immediate evaluation. Neonates with hyperleukocytosis are at risk of leukostasis and the associated severe complications, including respiratory distress, myocardial ischemia, hyperuricemia, acute renal failure, infarction, and hemorrhage. Differentiating leukemia and leukemoid reactions in neonates presenting with elevated TLC is challenging but critical. We present a unique case of a preterm male neonate with hyperleukocytosis, initially suspected to have an underlying malignancy. The neonate's clinical course was complicated by respiratory distress syndrome and anemia of prematurity, necessitating neonatal intensive care unit management. Further investigation revealed high human herpesvirus 6 (HHV-6) DNA levels in the whole blood, leading to a chromosomally integrated HHV-6 (ciHHV-6) diagnosis. CiHHV-6 is characterized by HHV-6 DNA integration into the host genome. Accurate diagnosis relies on whole-blood quantitative PCR, distinguishing ciHHV-6 from an active infection. The neonate remained asymptomatic, and antiviral treatment was deemed unnecessary. This case underscores the importance of recognizing ciHHV-6 as a potential cause of hyperleukocytosis in neonates and highlights the value of whole-blood PCR for differentiation. Understanding the spectrum of HHV-6 infection in neonates is vital for appropriate management and prognostication. [ABSTRACT FROM AUTHOR]

Leukocytosis in neonates can occur because of infectious, inflammatory, malignant, or physiological processes. Hyperleukocytosis is defined as a total leukocyte count (TLC) exceeding 100,000 per mm3, warranting immediate evaluation. Neonates with hyperleukocytosis are at risk of leukostasis and the associated severe complications, including respiratory distress, myocardial ischemia, hyperuricemia, acute renal failure, infarction, and hemorrhage. Differentiating leukemia and leukemoid reactions in neonates presenting with elevated TLC is challenging but critical. We present a unique case of a preterm male neonate with hyperleukocytosis, initially suspected to have an underlying malignancy. The neonate’s clinical course was complicated by respiratory distress syndrome and anemia of prematurity, necessitating neonatal intensive care unit management. Further investigation revealed high human herpesvirus 6 (HHV-6) DNA levels in the whole blood, leading to a chromosomally integrated HHV-6 (ciHHV-6) diagnosis. CiHHV-6 is characterized by HHV-6 DNA integration into the host genome. Accurate diagnosis relies on whole-blood quantitative PCR, distinguishing ciHHV-6 from an active infection. The neonate remained asymptomatic, and antiviral treatment was deemed unnecessary. This case underscores the importance of recognizing ciHHV-6 as a potential cause of hyperleukocytosis in neonates and highlights the value of whole-blood PCR for differentiation. Understanding the spectrum of HHV-6 infection in neonates is vital for appropriate management and prognostication.

BackgroundAlthough fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders.ObjectiveThe main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up.MethodsA retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed.ResultsA total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0).ConclusionMS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.

Background and Objectives: Infectious agents are considered one of the possible etiological factors of systemic lupus erythematosus (SLE). It has been suggested that human herpesvirus type 6 (HHV-6) may trigger autoimmune disorders, but few studies have been conducted on the relationship between this virus and autoimmune diseases, especially SLE. The present study aimed to compare the frequency of HHV-6 infection between SLE patients and healthy individuals. Materials and Methods: Serum samples were collected from 60 healthy people and 60 SLE patients referred to the rheumatology clinic of Shahid-Beheshti Hospital, Kashan, Iran, from January 2020 to January 2021. The following data were collected from the medical records of patients: sex; age; duration of disease; SLE clinical manifestations; and disease activity. After the extraction of viral DNA from samples, a nested polymerase chain reaction (PCR) test was performed to detect HHV-6. Results: HHV-6 was detected in 12 SLE patients (20%) and in 8 healthy individuals (13.3%). A significant correlation was not obtained between SLE and the presence of HHV-6 (P = 0.09). There was no correlation between musculoskeletal involvements, skin lesions, renal manifestations, and hematological manifestations with the presence of HHV-6 (P˃0.05). HHV-6 was detected more frequently in patients with active lupus than in patients with quiescent disease, but this difference was not significant (P=0.08). Conclusion: Although patients with SLE had a higher prevalence of HHV-6 compared with healthy people, there is no strong link between HHV-6 infection and SLE. Future research is necessary because this data does not support the hypothesis that human herpesvirus 6 plays a role in the pathogenesis of SLE. [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]

Background: Human herpesvirus 6 (HHV-6) is a double-stranded DNA virus well established in the clinical literature to cause the near-universal childhood infection roseola infantum (exanthema subitum/sixth disease). Primary HHV-6 infection has been reported to cause meningoencephalitis in pediatric patients, although generally in the immunocompromised. Case Description: The authors treated an immunocompetent 18-month-old female who transferred to our institution for a higher level of care given concerns for meningitis in the setting of decreased level of arousal (Glasgow Coma Scale 12), and bradycardia 9 days after the onset of nasal congestion, fatigue, and repeated bouts of emesis. Outside hospital cerebrospinal fluid (CSF) studies were notable for hypoglycorrhachia, elevated protein, elevated nucleated cells with a mononuclear predominance, and a meningitis polymerase chain reaction panel that was positive only for HHV-6. Brain magnetic resonance imaging with and without contrast revealed a basal cistern predominant leptomeningeal enhancement pattern as well as moderate ventriculomegaly with associated periventricular edema concerning acute communicating hydrocephalus. Considering the CSF studies, neuroimaging, and recent travel history to Mexico, central nervous system (CNS) tuberculosis (TB) was the leading suspicion, and antimicrobial therapy was initiated for this presumptive diagnosis with culture data only proving the TB suspicion correct after nearly 2 months in culture. Anti-viral therapy was initially not felt to be necessary as the HHV-6 was interpreted as incidental and not a cause of symptomatic meningitis in our immunocompetent host. The patient's hydrocephalus was treated with temporary CSF diversion followed by performance of an endoscopic third ventriculostomy. Despite appropriate hydrocephalus management, clinical improvement ultimately seemed to correlate with the initiation of antiviral therapy. Conclusion: The authors present this case and review the literature on HHV-6-associated CNS infections with the goal of informing the neurosurgeon about this often clinically underestimated pathogen. [ABSTRACT FROM AUTHOR]

Abstract Objective Inflammatory bowel disease (IBD) is closely related to stress and fatigue. Human herpesvirus 6B (HHV‐6B) is reactivated by stress and fatigue and is associated with IBD. This study aimed to clarify the relationship between IBD and HHV‐6B. Methods Antibody titers to SITH‐1, a protein specific to HHV‐6B latent infection, were measured in 163 patients with IBD (107 with ulcerative colitis [UC] and 56 with Crohn's disease [CD]); clinical and endoscopic scores and depression scores of UC and CD were analyzed to examine the relationship between SITH‐1 and IBD. The SITH‐1 cut‐off value was set as 1.96, according to known reports. Results In patients with UC, C‐reactive protein (CRP) level was significantly higher (1.5 vs 0.6 mg/L, P = 0.006) and disease exacerbation within 6 months after entry was significantly more common in the SITH‐1 (+) group (20% vs 0%, P

Multiple sclerosis (MS) is an immune inflammatory disease that causes demyelination of the white matter of the central nervous system. It is generally accepted that the etiology of MS is multifactorial and believed to be a complex interplay between genetic susceptibility, environmental factors, and infectious agents. While the exact cause of MS is still unknown, increasing evidence suggests that disease development is the result of interactions between genetically susceptible individuals and the environment that lead to immune dysregulation and CNS inflammation. Genetic factors are not sufficient on their own to cause MS, and environmental factors such as viral infections, smoking, and vitamin D deficiency also play important roles in disease development. Several pathogens have been implicated in the etiology of MS, including Epstein–Barr virus, human herpesvirus 6, varicella-zoster virus, cytomegalovirus, Helicobacter pylori, Chlamydia pneumoniae, and Borrelia burgdorferi. Although vastly different, viruses and bacteria can manipulate host gene expression, causing immune dysregulation, myelin destruction, and neuroinflammation. This review emphasizes the pathogenic triggers that should be considered in MS progression.

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.

Background and Objectives: Infectious agents are considered one of the possible etiological factors of systemic lupus erythematosus (SLE). It has been suggested that human herpesvirus type 6 (HHV-6) may trigger autoimmune disorders, but few studies have been conducted on the relationship between this virus and autoimmune diseases, especially SLE. The present study aimed to compare the frequency of HHV-6 infection between SLE patients and healthy individuals. Materials and Methods: Serum samples were collected from 60 healthy people and 60 SLE patients referred to the rheumatology clinic of Shahid-Beheshti Hospital, Kashan, Iran, from January 2020 to January 2021. The following data were collected from the medical records of patients: sex; age; duration of disease; SLE clinical manifestations; and disease activity. After the extraction of viral DNA from samples, a nested polymerase chain reaction (PCR) test was performed to detect HHV-6. Results: HHV-6 was detected in 12 SLE patients (20%) and in 8 healthy individuals (13.3%). A significant correlation was not obtained between SLE and the presence of HHV-6 (P = 0.09). There was no correlation between musculoskeletal involvements, skin lesions, renal manifestations, and hematological manifestations with the presence of HHV-6 (P˃0.05). HHV-6 was detected more frequently in patients with active lupus than in patients with quiescent disease, but this difference was not significant (P=0.08). Conclusion: Although patients with SLE had a higher prevalence of HHV-6 compared with healthy people, there is no strong link between HHV-6 infection and SLE. Future research is necessary because this data does not support the hypothesis that human herpesvirus 6 plays a role in the pathogenesis of SLE.

Objective: Inflammatory bowel disease (IBD) is closely related to stress and fatigue. Human herpesvirus 6B (HHV‐6B) is reactivated by stress and fatigue and is associated with IBD. This study aimed to clarify the relationship between IBD and HHV‐6B. Methods: Antibody titers to SITH‐1, a protein specific to HHV‐6B latent infection, were measured in 163 patients with IBD (107 with ulcerative colitis [UC] and 56 with Crohn's disease [CD]); clinical and endoscopic scores and depression scores of UC and CD were analyzed to examine the relationship between SITH‐1 and IBD. The SITH‐1 cut‐off value was set as 1.96, according to known reports. Results: In patients with UC, C‐reactive protein (CRP) level was significantly higher (1.5 vs 0.6 mg/L, P = 0.006) and disease exacerbation within 6 months after entry was significantly more common in the SITH‐1 (+) group (20% vs 0%, P < 0.001). In the subanalysis comparing with and without UC exacerbation, the optimal cut‐off value for SITH‐1 to detect UC exacerbation was 3.44 (area under the curve: 0.81; 95% confidence interval: 0.72–0.90). CRP levels, SITH‐1 levels, and disease activity scores by the clinical or endoscopic index were significantly higher in the exacerbation group than in the non‐exacerbation group (2.6 vs 0.9 mg/L, P = 0.03; 4.90 vs 1.71, P < 0.001; 4 vs 3, P = 0.03; 5 vs 3, P = 0.02; respectively). Conclusion: Patients with UC with high titers of SITH‐1 have high disease activity and frequent disease exacerbation. SITH‐1 can be associated with UC disease activity. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia. While pathologic hallmarks, such as extracellular beta-amyloid plaques, are well-characterized in affected individuals, the pathogenesis that causes plaque formation and eventual cognitive decline is not well understood. A recent resurgence of the decades-old "infectious hypothesis" has garnered increased attention on the potential role that microbes may play in AD. In this theory, it is thought that pathogens such as viruses may act as seeds for beta-amyloid aggregation, ultimately leading to plaques. Interest in the infectious hypothesis has also spurred further investigation into additional characteristics of viral infection that may play a role in AD progression, such as neuroinflammation, latency, and viral DNA integration. While a flurry of research in this area has been recently published, with herpesviruses being of particular interest, the role of pathogens in AD remains controversial. In this review, the insights gained thus far into the possible role of herpesviruses in AD are summarized. The challenges and potential future directions of herpesvirus research in AD and dementia are also discussed. [ABSTRACT FROM AUTHOR]

Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3-4 weeks before onset of vaccine meningitis may be a risk factor in some cases.

Introduction: Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. Methods: A scoping review with the PubMed query "(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))" was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. Results: Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. Conclusion: HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease, and the etiology is still unclear. Some studies have indicated that viral infection might contribute to the development of SLE. Methods A total of 105 individuals with SLE and 110 matched healthy controls were tested for EBV-specific DNA fragments in peripheral blood monocytes by PCR-Southern blotting. The expression of EBV-encoded genes was determined by RT-PCR and Southern blotting in EBV-positive patients. Serum EBV-specific IgM antibody was determined by ELISA. HHV-6 DNA in peripheral blood monocytes of those SLE patients and normal controls was tested by nested PCR. Results Statistical analysis showed that the EBV-positive rate of SLE patients was significantly higher than that of the control group (χ2 = 87.329, P = 0), while the difference in the HHV-6-positive rate between the two groups was not significant (P > 0.05). An association of EBV and HHV-6 positivity in SLE patients was found (P = 0, r = 0.38). The EBV IgM level was significantly higher in SLE patients than in healthy controls (χ2 = 25.184, P = 0). Forty-two of the 75 EBV DNA-positive specimens were positive for EBNA2 mRNA, and an association between EBV EBNA2 mRNA and anti-Sm antibody positivity was found (P = 0, r = 0.409). LMP1 mRNA was positive in 2 SLE patients with active phase, and no LMP2A mRNA expression was detected in EBV DNA-positive specimens. EBV early gene BARF1 mRNA was detected in 2 cases of EBV-positive SLE patients, and these 2 patients were also HHV-6 DNA positive. Thirty-eight patients were BcLF1 mRNA positive, and 33 of them were HHV-6 positive as well. These factors were associated (χ2 = 15.734, P = 0). The expression of the EBV immediate early gene BZLF1 was negative in all 75 EBV-positive SLE patients. Conclusions The results suggest that EBV infection might be related to the occurrence of SLE. Although there is no direct evidence that HHV-6 infection is associated with the development of SLE, EBV and HHV-6 infection may have a coacceleration effect in SLE patients. This study provides a new theoretical and experimental basis for the study of viral etiology and the prevention and treatment of SLE.

Abstract Background Immunocompromised patients face reactivation of latent viruses that increase the risk of morbidity. Aim The study aimed to detect human herpes virus 6 (HHV-6) reactivation among allogeneic (allo) and autologous (auto) hematopoietic stem cell transplant (HSCT) recipients and to correlate potentially attributed clinical manifestations to HHV-6 DNA plasma level. Methods A prospective study included all (forty) patients undergoing allo and auto-HSCT from Jan 2020 till June 2022. Plasma samples were collected for HHV-6 serology, and for HHV-6 quantitative PCR at post-transplantation weeks 2, 4, 6. Demographic and clinical data were recorded. Results Out of 40 peripheral blood stem cell transplant (PBSCT) recipients, 34 (85%) were HHV-6 IgG positive pre-HSCT. Of which, fourteen patients (14/34, 41.2%) showed positive HHV-6 DNaemia. HHV-6 DNAemia (15/40, 37.5%) was significantly higher among allo (8/12, 66.7%) versus auto (7/28, 25%) HSCT recipients (p = 0.030). Patients with HHV-6 DNAemia developed fever, delayed engraftment and bone marrow suppression in 6/15, 40%, thrombocytopenia (5/15, 33.3%), rash and pneumonitis (2/15, 13.3%), acute GVHD (aGVHD) (1/15, 6.7%). HHV-6 DNAemia ranged from 101 to 102,000 copies/mL. Univariate analysis identified conditioning with busulfan–cyclophosphamide as a significant risk (p = 0.043), while receiving BEAM protocol was a protective factor (p = 0.045). In multivariate analysis, receiving BEAM protocol retained significance (p = 0.040). Conclusion Frequent HHV-6 reactivation was detected after HSCT, especially in allo-HSCT recipients with clinical manifestations which could not be otherwise explained. To our best knowledge this is the first study of HHV6 reactivation in HSCT recipients from Egypt. Raising awareness for HHV-6 reactivation manifestations and screening in HSCT recipients could be lifesaving.

Abstract We performed virological analysis of resected brain tissues from a patient with temporal lobe epilepsy associated with mesial temporal sclerosis after febrile status epilepticus caused by human herpesvirus 6 infection. The patient had febrile status epilepticus at 9 months of age associated with human herpesvirus 6 infection. Magnetic resonance imaging revealed reduced water diffusion in the right temporal lobe and hippocampus. Polymerase chain reaction analysis detected 1.6 × 105 copies/μg of human herpesvirus 6 DNA in whole blood, but none in the cerebrospinal fluid. The patient developed temporal lobe epilepsy associated with mesial temporal sclerosis at 67 months of age, necessitating surgical treatment. Anterior temporal lobectomy was performed at 171 months of age. Real‐time polymerase chain reaction analysis of resected brain tissues revealed no viral DNA. In our patient, human herpesvirus 6 infection triggered febrile status epilepticus, while direct evidence to prove contribution of HHV‐6 to the development of MTS was not obtained.

To investigate viruses in measles‐negative cases, 221 measles‐suspected samples collected in Gyeonggi Province, South Korea were tested using a real‐time PCR assay. Rubella virus was not detected. However, 11 cases of parvovirus B19 (5.0%), 47 cases of human herpesvirus 6 (21.3%), 25 cases of human herpesvirus 7 (11.3%), and one case of co‐infection with parvovirus B19 and human herpesvirus 7 were confirmed, as were eight cases of co‐infection with human herpesvirus 6 and human herpesvirus 7. This study showed that parvovirus B19, human herpesvirus 6, and human herpesvirus 7 should be considered by physicians for the diagnosis of measles‐suspected patients. [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.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease of unknown origin. The current paradigm is that disease develops in genetically susceptible individuals, influenced by environmental factors. Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have particularly strong associations with the disease. Both viruses are typically acquired during childhood, decades before MS presents. However, in patients with pediatric MS, the temporal window between viral acquisition and disease onset is shortened, which may provide insights into the association of herpesviruses with MS. OBJECTIVE: To compare the frequency of EBV and HHV-6 in the saliva of a cohort of pediatric MS patients and age-matched controls. METHODS: The study enrolled 32 pediatric MS patients and 42 controls and evaluated saliva for HHV-6 u57 and EBV lmp-1 amplification by droplet digital polymerase chain reaction (ddPCR). RESULTS: Pediatric MS patients did not differ from controls in the frequency or magnitude of salivary viral shedding. During the assessment of EBV positivity, distinct profiles emerged that correlated with target amplicon mutations. CONCLUSIONS: None of these mutations were evident in EBV-positive samples from pediatric MS patients, whereas they were present in pediatric controls, in addition to MS and control adults, suggesting differential host-immune control of EBV in this pediatric MS cohort.

The literature review is devoted to the modern concept of human betaherpesvirus 6 (human herpesvirus 6; HHV-6). The analysis of the literature mainly for the last five years was carried out. The article provides a brief background on the history of the discovery of viruses, highlights the taxonomy of HHV-6, new views on the etiological features of the HHV-6A and HHV-6B viruses, in particular, the possibility of their gene integration. Differences between HHV-6A and B are described. Modern views on the etiological relationship of various diseases of the central and peripheral nervous system, а heart, other organs and systems with HHV-6A and HHV-6B are presented. There have been cases of infectious mononucleosis associated with HHV-6, as well as exanthemа subitum that is mostly typical for children under 2 years old. Modern ideas about the possibilities and problems of HHV-6 infection laboratory diagnosis and treatment of children and adult are given. Obtained data points out necessary of a unified protocol creation for the examination and treatment of HHV-6.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease, and the etiology is still unclear. Some studies have indicated that viral infection might contribute to the development of SLE. Methods: A total of 105 individuals with SLE and 110 matched healthy controls were tested for EBV-specific DNA fragments in peripheral blood monocytes by PCR-Southern blotting. The expression of EBV-encoded genes was determined by RT-PCR and Southern blotting in EBV-positive patients. Serum EBV-specific IgM antibody was determined by ELISA. HHV-6 DNA in peripheral blood monocytes of those SLE patients and normal controls was tested by nested PCR. Results: Statistical analysis showed that the EBV-positive rate of SLE patients was significantly higher than that of the control group (χ2 = 87.329, P = 0), while the difference in the HHV-6-positive rate between the two groups was not significant (P > 0.05). An association of EBV and HHV-6 positivity in SLE patients was found (P = 0, r = 0.38). The EBV IgM level was significantly higher in SLE patients than in healthy controls (χ2 = 25.184, P = 0). Forty-two of the 75 EBV DNA-positive specimens were positive for EBNA2 mRNA, and an association between EBV EBNA2 mRNA and anti-Sm antibody positivity was found (P = 0, r = 0.409). LMP1 mRNA was positive in 2 SLE patients with active phase, and no LMP2A mRNA expression was detected in EBV DNA-positive specimens. EBV early gene BARF1 mRNA was detected in 2 cases of EBV-positive SLE patients, and these 2 patients were also HHV-6 DNA positive. Thirty-eight patients were BcLF1 mRNA positive, and 33 of them were HHV-6 positive as well. These factors were associated (χ2 = 15.734, P = 0). The expression of the EBV immediate early gene BZLF1 was negative in all 75 EBV-positive SLE patients. Conclusions: The results suggest that EBV infection might be related to the occurrence of SLE. Although there is no direct evidence that HHV-6 infection is associated with the development of SLE, EBV and HHV-6 infection may have a coacceleration effect in SLE patients. This study provides a new theoretical and experimental basis for the study of viral etiology and the prevention and treatment of SLE. [ABSTRACT FROM AUTHOR]

Background: Immunocompromised patients face reactivation of latent viruses that increase the risk of morbidity. Aim: The study aimed to detect human herpes virus 6 (HHV-6) reactivation among allogeneic (allo) and autologous (auto) hematopoietic stem cell transplant (HSCT) recipients and to correlate potentially attributed clinical manifestations to HHV-6 DNA plasma level. Methods: A prospective study included all (forty) patients undergoing allo and auto-HSCT from Jan 2020 till June 2022. Plasma samples were collected for HHV-6 serology, and for HHV-6 quantitative PCR at post-transplantation weeks 2, 4, 6. Demographic and clinical data were recorded. Results: Out of 40 peripheral blood stem cell transplant (PBSCT) recipients, 34 (85%) were HHV-6 IgG positive pre-HSCT. Of which, fourteen patients (14/34, 41.2%) showed positive HHV-6 DNaemia. HHV-6 DNAemia (15/40, 37.5%) was significantly higher among allo (8/12, 66.7%) versus auto (7/28, 25%) HSCT recipients (p = 0.030). Patients with HHV-6 DNAemia developed fever, delayed engraftment and bone marrow suppression in 6/15, 40%, thrombocytopenia (5/15, 33.3%), rash and pneumonitis (2/15, 13.3%), acute GVHD (aGVHD) (1/15, 6.7%). HHV-6 DNAemia ranged from 101 to 102,000 copies/mL. Univariate analysis identified conditioning with busulfan–cyclophosphamide as a significant risk (p = 0.043), while receiving BEAM protocol was a protective factor (p = 0.045). In multivariate analysis, receiving BEAM protocol retained significance (p = 0.040). Conclusion: Frequent HHV-6 reactivation was detected after HSCT, especially in allo-HSCT recipients with clinical manifestations which could not be otherwise explained. To our best knowledge this is the first study of HHV6 reactivation in HSCT recipients from Egypt. Raising awareness for HHV-6 reactivation manifestations and screening in HSCT recipients could be lifesaving. [ABSTRACT FROM AUTHOR]

The Human Betaherpesviruses HHV-5 and HHV-6 are quite inimical in immunocompromised hosts individually. A co-infection of both has been surmised to be far more disastrous. This can be attributed to a synergetic effect of their combined pathologies. While there have been attempts to develop a vaccine against each virus, no efforts were made to contrive an effective prophylaxis for the highly detrimental co-infection. In this study, an ensemble of viral envelope glycoproteins from both the viruses was utilized to design a multi-epitope vaccine using immunoinformatics tools. A collection of bacterial protein toll-like receptor agonists (BPTAs) was screened to identify a highly immunogenic adjuvant for the vaccine construct. The constructed vaccine was analysed using an array of methodologies ranging from World population coverage analysis to Immune simulation, whose results indicate high vaccine efficacy and stability. Furthermore, codon optimization and in silico cloning analysis were performed to check for efficient expression in a bacterial system. Collectively, these findings demonstrate the potential of the constructed vaccine to elicit an immune response against HHV-5 and HHV-6, thus supporting the viability of in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

We performed virological analysis of resected brain tissues from a patient with temporal lobe epilepsy associated with mesial temporal sclerosis after febrile status epilepticus caused by human herpesvirus 6 infection. The patient had febrile status epilepticus at 9 months of age associated with human herpesvirus 6 infection. Magnetic resonance imaging revealed reduced water diffusion in the right temporal lobe and hippocampus. Polymerase chain reaction analysis detected 1.6 × 105 copies/μg of human herpesvirus 6 DNA in whole blood, but none in the cerebrospinal fluid. The patient developed temporal lobe epilepsy associated with mesial temporal sclerosis at 67 months of age, necessitating surgical treatment. Anterior temporal lobectomy was performed at 171 months of age. Real‐time polymerase chain reaction analysis of resected brain tissues revealed no viral DNA. In our patient, human herpesvirus 6 infection triggered febrile status epilepticus, while direct evidence to prove contribution of HHV‐6 to the development of MTS was not obtained. [ABSTRACT FROM AUTHOR]

Varicella-zoster virus (VZV) infection in adults or immunocompromised patients has a more severe presentation compared to the mild disease in children. To the best of our knowledge, no reports have described the clinical course of VZV pneumonia focusing on time course of skin rash, chest computed tomography (CT) findings, and viral load. Furthermore, no reports have described the reactivation of human herpes virus 6 (HHV-6) in VZV pneumonia. Here, we report a case of severe VZV pneumonia that resulted in reactivation of HHV-6 in a patient with rheumatoid arthritis (RA). A 66-year-old female treated for RA was admitted to our hospital with papules. Her chest CT showed granular infiltrates, micronodules, and ground-glass opacities. The day after admission, because the typical skin rashes and chest CT findings were observed, she was diagnosed with VZV pneumonia and treated with acyclovir. Her skin rash then crusted over five days and entered the healing process, whereas it took approximately two weeks for her respiratory condition and chest CT findings to improve. In addition, VZV deoxyribonucleic acid (DNA) gradually decreased with treatment. On the 34th day of admission, VZV DNA was not found in the serum sample but remained in the sputum sample. Furthermore, although reactivation of HHV-6 was observed, viremia resolved without treatment. Clinicians should be able to recognize the differences in the improvement of skin rashes, respiratory status, and chest CT findings. In addition, treatment for HHV-6 reactivation should be carefully determined for each case.

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.

In order to determine the role of human herpesvirus 6 (HHV-6) in human disease, several confounding factors, including methods of detection, types of controls, and the ubiquitous nature of the virus, must be considered. This is particularly problematic in the case of cancer, in which rates of detection vary greatly among studies. To determine what part, if any, HHV-6 plays in oncogenesis, a review of the literature was performed. There is evidence that HHV-6 is present in certain types of cancer; however, detection of the virus within tumor cells is insufficient for assigning a direct role of HHV-6 in tumorigenesis. Findings supportive of a causal role for a virus in cancer include presence of the virus in a large proportion of cases, presence of the virus in most tumor cells, and virus-induced in-vitro cell transformation. HHV-6, if not directly oncogenic, may act as a contributory factor that indirectly enhances tumor cell growth, in some cases by cooperation with other viruses. Another possibility is that HHV-6 may merely be an opportunistic virus that thrives in the immunodeficient tumor microenvironment. Although many studies have been carried out, it is still premature to definitively implicate HHV-6 in several human cancers. In some instances, evidence suggests that HHV-6 may cooperate with other viruses, including EBV, HPV, and HHV-8, in the development of cancer, and HHV-6 may have a role in such conditions as nodular sclerosis Hodgkin lymphoma, gastrointestinal cancer, glial tumors, and oral cancers. However, further studies will be required to determine the exact contributions of HHV-6 to tumorigenesis.

In order to determine the role of human herpesvirus 6 (HHV-6) in human disease, several confounding factors, including methods of detection, types of controls, and the ubiquitous nature of the virus, must be considered. This is particularly problematic in the case of cancer, in which rates of detection vary greatly among studies. To determine what part, if any, HHV-6 plays in oncogenesis, a review of the literature was performed. There is evidence that HHV-6 is present in certain types of cancer; however, detection of the virus within tumor cells is insufficient for assigning a direct role of HHV-6 in tumorigenesis. Findings supportive of a causal role for a virus in cancer include presence of the virus in a large proportion of cases, presence of the virus in most tumor cells, and virus-induced in-vitro cell transformation. HHV-6, if not directly oncogenic, may act as a contributory factor that indirectly enhances tumor cell growth, in some cases by cooperation with other viruses. Another possibility is that HHV-6 may merely be an opportunistic virus that thrives in the immunodeficient tumor microenvironment. Although many studies have been carried out, it is still premature to definitively implicate HHV-6 in several human cancers. In some instances, evidence suggests that HHV-6 may cooperate with other viruses, including EBV, HPV, and HHV-8, in the development of cancer, and HHV-6 may have a role in such conditions as nodular sclerosis Hodgkin lymphoma, gastrointestinal cancer, glial tumors, and oral cancers. However, further studies will be required to determine the exact contributions of HHV-6 to tumorigenesis.

Herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and human herpesvirus 6 (HHV-6) cause severe infections in immunocompromised hosts. Interventions to optimize virus-specific adaptive immunity may have advantages over antivirals in the prophylaxis and treatment of these infections. We sought to review adaptive immune responses and methods for assessing and replenishing cellular and humoral immunity to HSV, VZV, and HHV-6 in solid organ transplant and hematopoietic cell transplant recipients. We searched PubMed for relevant studies on immune responses to HSV, VZV, and HHV-6 as well as studies describing methods for evaluating and restoring cell-mediated immunity to other double-stranded DNA viruses in transplant recipients. Recent studies, randomized controlled trials, and investigations highlighting key concepts in clinical virology were prioritized for inclusion. We describe the mechanisms of adaptive immunity to HSV, VZV, and HHV-6 and limitations of antivirals as prophylaxis and treatment for these infections in solid organ transplant and hematopoietic cell transplant recipients. We review methods for measuring and restoring cellular immunity to double-stranded DNA viruses; their potential applications to management of HSV, VZV, and HHV-6 in immunocompromised hosts; and barriers to clinical use. Vaccination and virus-specific T cell therapies are discussed in detail. The growing repertoire of diagnostic and therapeutic techniques focused on virus-specific adaptive immunity provides a novel approach to management of viral infections in transplant recipients. Investigations to optimize such interventions specifically in HSV, VZV, and HHV-6 are needed. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: Human herpesvirus 6 (HHV-6) is neurophilic, and its relationship with Alzheimer's disease (AD) remains controversial. This study aimed to examine the relationships between HHV-6 and cognitive abilities in elderly people aged 60 years or above from communities in Shenzhen. Methods: We recruited participants from 10 community health service centers in Shenzhen. Participants were divided into case and control groups according to Mini-Mental State Examination (MMSE) scale standards and were included in this study with 1:1 matching based on sex and age (± 3 years). The HHV-6 gene was detected by real-time fluorescent quantitative PCR, and the HHV-6 copy number was quantified. Results: A total of 580 participants (cases, n = 290; controls, n = 290), matched for gender and age was included in this study. A positive HHV-6 test was not associated with a significant difference in global cognitive performance (ORadjusted = 1.651, 95% CI = 0.671–4.062). After adjusting for gender, age, education, Pittsburgh Sleep Quality Index (PSQI) score, homocysteine (Hcy) and glycosylated hemoglobin (HbA1c), the results of multiple linear regression showed that there was a statistically negative correlation between HHV-6 copy number and orientation (βadjusted = −0.974, p = 0.013), attention and calculation (βadjusted = −1.840, p < 0.001), and language (βadjusted = −2.267, p < 0.001). The restricted cubic spline (RCS) model results showed that there was a nonlinear dose–response relationship between HHV-6 log10-transformed copies and orientation (poverall = 0.003, pnonliner = 0.045), attention and calculation (poverall < 0.001, pnonliner < 0.001), and language (poverall < 0.001, pnonliner = 0.016). Conclusions: HHV-6 infection significantly associated with orientation, attention and calculation, and language in elderly individuals. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration. [ABSTRACT FROM AUTHOR]

Adenoids and tonsils have gained interest as a new in vivo model to study local immune functions and virus reservoirs. Especially herpesviruses are interesting because their prevalence and persistence in local lymphoid tissue are incompletely known. Our aim was to study herpesvirus and common respiratory virus infections in nonacutely ill adenotonsillar surgery patients. Adenoid and/or palatine tonsil tissue and nasopharyngeal aspirate (NPA) samples were collected from elective adenoidectomy (n = 45) and adenotonsillectomy (n = 44) patients (median age: 5, range: 1–20). Real‐time polymerase chain reaction was used to detect 22 distinct viruses from collected samples. The overall prevalence of herpesviruses was 89% and respiratory viruses 94%. Human herpesviruses 6 (HHV6), 7 (HHV7), and Epstein–Barr virus (EBV) were found, respectively, in adenoids (33%, 26%, 25%), tonsils (45%, 52%, 23%), and NPA (46%, 38%, 25%). Copy numbers of the HHV6 and HHV7 genome were significantly higher in tonsils than in adenoids. Patients with intra‐adenoid HHV6 were younger than those without. Detection rates of EBV and HHV7 showed agreement between corresponding sample types. This study shows that adenoid and tonsil tissues commonly harbor human herpes‐ and respiratory viruses, and it shows the differences in virus findings between sample types. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a global health concern with a complex etiology involving genetic, environmental and infectious factors. The exact cause of MDD remains unknown. The present study explored the association between genetic factors, human herpesvirus 6 (HHV-6) and MDD. The present study analyzed single nucleotide polymorphisms (SNPs) and HHV-6 viral load in oral buccal samples from patients with MDD (with and without blood relatives with MDD) and healthy controls. The study used high-resolution melt analysis to examine rs40184 (C>T) in the solute carrier family 6 member 3 (SLC6A31) gene, rs6265 (C>T) in the brain-derived neurotrophic factor (BDNF) gene and rs9383046 (G>A) in the jumonji and AT-rich interaction domain-containing 2 (JARID2) gene. HHV-6 infection and viral load was assessed using the quantitative PCR. Whole-exome sequencing was used to examine SNPs. The variant alleles of SNPs rs40184 [18/40 (45.00) vs. 29/238 (12.55%)] and rs6265 [30/54 (55.46) vs. 117/292 (40.06%)] were significantly more common in patients with MDD than in healthy controls, indicating they may be probable hereditary risk factors for MDD. HHV-6 positivity was significantly more common in carriers of the G/A genotype (12/15, 80%) than carriers of the G/G genotype (75/363, 20.7%) for rs9383046, implying that genetic variations may affect HHV-6 risk and MDD onset. Similarly, HHV-6 viral loads were significantly higher in carriers of the G/A genotype (99,990.85±118,392.64 copies/ng DNA) than carriers of the G/G genotype (48,249.30±101,216.28 copies/ng DNA) for rs9383046. Whole-exome sequencing identified two SNPs in JARID2 (rs11757092 and rs9383050) associated with MDD, highlighting its genetic complexity. The present study helps explain the complex interactions between HHV-6 infection, genetics and MDD onset, improving understanding of how SNPs in JARID2 contribute to HHV-6 infection and MDD onset; these findings may impact future approaches to diagnosing and treating MDD., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Bumrungthai et al.)

Coronary spasm has been suggested to be the underlying mechanism of chest pain in patients with myocarditis and unobstructed coronary arteries. Here we sought to investigate a potential association between virus type and coronary spasm endotype in patients with biopsy-proven viral myocarditis. A total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened. Viral myocarditis defined as (immuno-)histological evidence of myocardial inflammation and proof of viral genome by PCR was confirmed in 114 patients. Of these, 34 patients had undergone additional intracoronary acetylcholine (ACh) testing and served as the final study cohort. Patients in this study were 51 ± 27 years old, 41% were female and mean left ventricular ejection fraction was 58 ± 23%. Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%). ACh testing revealed epicardial spasm in 10 patients (29%) and microvascular spasm in 11 patients (32%). The rate of coronary spasm was higher in patients with PVB19-associated myocarditis compared to those with HHV6-associated myocarditis (80% vs. 33%, p = 0.031). In particular, there was a higher prevalence of microvascular spasm in patients with PVB19 compared to HHV6 infection (45% vs. 0%, p = 0.018). Coronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients. We observed a particular association of microvascular spasm with PVB19 infection. • Patients with viral myocarditis often present with chest pain. • Most frequently in lymphocytic myocarditis, PVB19 and HHV6 DNA is detected. • Coronary artery spasm could contribute to chest pain in myocarditis. • We observed an association of PVB19 DNA-positive myocarditis with coronary microvascular spasm. [ABSTRACT FROM AUTHOR]

Introduction: Evidence points to viral infections as possible triggers of autoimmune thyroid disease (AITD), but little is known about the prevalence of common viruses in the thyroid gland. Using a novel approach based on virus enrichment in multiple cell lines followed by detection of the viral genome and visualization of viral proteins, we investigated the presence of multiple human viruses in thyroid tissue from AITD patients and controls. Methods: Thyroid tissue was collected by core needle biopsy or during thyroid surgery from 35 patients with AITD (20 Graves' disease and 15 Hashimoto's thyroiditis). Eighteen thyroid tissue specimens from patients undergoing neck surgery for reasons other than thyroid autoimmunity served as controls. Specimens were tested for the presence of ten different viruses. Enteroviruses and human herpesvirus 6 were enriched in cell culture before detection by PCR and immunofluorescence, while the remaining viruses were detected by PCR of biopsied tissue. Results: Forty of 53 cases (75%) carried an infectious virus. Notably, 43% of all cases had a single virus, whereas 32% were coinfected by two or more virus types. An enterovirus was found in 27/53 cases (51%), human herpesvirus 6 in 16/53 cases (30%) and parvovirus B19 in 12/53 cases (22%). Epstein-Barr virus and cytomegalovirus were found in a few cases only. Of five gastroenteric virus groups examined, only one was detected in a single specimen. Virus distribution was not statistically different between AITD cases and controls. Conclusion: Common human viruses are highly prevalent in the thyroid gland. This is the first study in which multiple viral agents have been explored in thyroid. It remains to be established whether the detected viruses represent causal agents, possible cofactors or simple bystanders. [ABSTRACT FROM AUTHOR]

Within the family Herpesviridae, sub-family b-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the b-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Human herpesvirus 6 (HHV‐6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) and may be associated with significant morbidity and mortality. Methods: The epidemiology of HHV‐6 infections and their impact on outcome after allo‐HSCT were retrospectively analyzed in 689 adult allo‐HSCT recipients (January 2015–December 2018). Chromosomal integration of HHV‐6 (ciHHV‐6) in the donor was retrospectively investigated to critically evaluate antiviral treatment strategies. Results: HHV‐6 DNA in any specimen was found in 89 patients. HHV‐6 infections (encephalitis (one), gastroenteritis (44), dermatitis (two), hepatitis (one), or pneumonitis (five)) were diagnosed in 53/689 patients (7.7%). Elevated levels of HHV‐6 DNA were found in 38 patients (5.5%). ciHHV‐6, analyzed in patients with HHV‐6 viral loads ≥104 copies/ml, was identified in four patients (10/38 patients; 10.5%). Two of those displayed copy numbers of HHV‐6 ranging from ≥2 × 105 to 2.5 × 106 copies/ml (HHV‐6A). Here, ciHHV‐6 was integrated into donor and not into the patients' cells. In this series of allo‐HSCT recipients, 10.5% of patients with blood viral loads of HHV‐6 showed ciHHV‐6. Conclusion: Screening of the donor for ciHHV‐6 before initiation of antiviral therapy is recommended. [ABSTRACT FROM AUTHOR]

Drug‐induced hypersensitivity syndrome (DiHS) is a severe drug eruption that can induce reactivation of herpesviruses such as human herpesvirus 6, resulting in symptom flare‐up and organ damage. DiHS is known as drug reaction with eosinophilia and systemic symptoms (DRESS) in Europe. We report three cases of DiHS that could have been triggered by mRNA‐based coronavirus disease 2019 (COVID‐19) vaccines. In these three patients, symptoms of DiHS developed 2–6 days after the first dose of an mRNA‐based COVID‐19 vaccine. Although there have been no reports of DiHS/DRESS induced by mRNA‐based COVID‐19 vaccines in domestic and international journals despite the progress in vaccination worldwide, we speculate that mRNA‐based COVID‐19 vaccines might have triggered the development of DiHS/DRESS in our patients. In the current coronavirus epidemic, it might be important to assess mRNA‐based COVID‐19 vaccination status and date of vaccination when evaluating a patient with DiHS/DRESS. [ABSTRACT FROM AUTHOR]