吉川 哲史

Human herpesviruses exhibit diverse pathogenic outcomes and the molecular reasons are not fully understood. Human herpesvirus 6B (HHV-6B) causes exanthema subitum and encephalitis, whereas the closely related HHV-6A is typically asymptomatic. Here, we show that cellular APOBEC3 enzymes restrict HHV-6A replication but not HHV-6B. HHV-6B expresses higher levels of the U28 protein, which binds multiple APOBEC3 proteins and promotes their relocalization and degradation. In contrast, HHV-6A fails to counteract APOBEC3 activity and accumulates extensive mutations in both cell- and patient-derived viral genomes. Individual APOBEC3 gene ablation enhances HHV-6A replication and reduces the viral mutation burden. Together, our studies suggest that differential susceptibility to APOBEC3 restriction may help to shape the evolvability and clinical manifestations of HHV-6A and HHV-6B.

BACKGROUND: Rotavirus vaccination effectively prevents severe rotavirus gastroenteritis; however, administration during neonatal hospitalization is often avoided because of theoretical concerns regarding vaccine-virus transmission. Data on the safety of in-hospital rotavirus vaccination in neonatal step-down care settings remain limited. METHODS: We conducted a 1-year prospective cohort study in a Japanese growing care unit, a step-down neonatal unit comparable to Level II-III neonatal intensive care units in the United States. Hospitalized infants were monitored for adverse events and vaccine-strain shedding after administration of monovalent rotavirus vaccine (RV1). Stool samples were collected weekly and analyzed using RV1 strain-specific real-time quantitative reverse transcription polymerase chain reaction targeting the NSP2 gene. Routine contact precautions, including gown and glove use for all patient care activities and environmental cleaning, were consistently implemented. RESULTS: Among 237 infants included in the analysis, 15 received a total of 19 doses of RV1 during hospitalization. RV1 vaccine-strain RNA was detected in 26 of 38 postvaccination stool samples (68.4%). No RV1 strain RNA was detected in unvaccinated infants or in samples collected before vaccination. No serious adverse events were observed, and no evidence of horizontal transmission was identified. Six vaccinated infants exceeded the upper age limit for vaccine initiation at discharge and would have missed vaccination opportunities without in-hospital vaccination. CONCLUSIONS: RV1 vaccination was not associated with detectable transmission or serious adverse events in a neonatal step-down care setting under routine contact precautions, supporting its potential safety and role in preventing missed vaccination opportunities among high-risk infants.

Severe acute encephalopathy/encephalitis (AE) associated with SARS-CoV-2 has been increasingly reported since the emergence of the Omicron variant. Several pediatric cases have shown the development of acute fulminant cerebral edema (AFCE) or hemorrhagic shock encephalopathy syndrome (HSES), which are linked to high morbidity and mortality. However, the underlying pathogenic mechanisms remain unclear. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from a pediatric patient with SARS-CoV-2-associated AE presenting with AFCE/HSES and compared the data with those from two patients with mild AE, one patient with febrile seizures due to non-SARS-CoV-2 pathogens, and publicly available pediatric COVID-19 datasets without neurological complications. During the acute phase, we observed a prominent expansion of B-cell populations, including distinct activated B-cell clusters. Cell-cell communication analysis identified macrophage migration inhibitory factor signaling, although it was not specific to SARS-CoV-2-associated AE. Notably, heat shock protein genes, particularly HSPA1A and HSPB1, were selectively upregulated across multiple immune cell types only in severe SARS-CoV-2-associated AE. Enzyme-linked immunosorbent assay confirmed significantly elevated plasma and serum protein levels of HSPA1A and HSPB1 during the acute phase. These findings highlight HSPA1A and HSPB1 as potential biomarkers of severe SARS-CoV-2-associated AE and suggest a pathogenic possible role for stress-response pathways.

BACKGROUND: Exanthem subitum (ES), a benign febrile exanthematous disease, is caused by primary human betaherpesvirus 6B (HHV-6B) infection. It may cause neurological complications, including complex febrile seizures (cFS), acute encephalopathy with biphasic seizures, and late reduced diffusion (AESD). cFS resolves spontaneously; however, AESD can pose severe sequelae. We aimed to elucidate AESD pathogenesis using a proteomic analysis. METHODS: Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), serum and cerebrospinal fluid (CSF) protein profiles were compared between patients with AESD and those with cFS (n = 3 or 4 per group). Metascape was used for enrichment analysis, and the selected proteins were validated using a large sample via enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 698 proteins were identified across all serum and CSF samples using LC-MS/MS. Nineteen serum proteins were differentially expressed in AESD and cFS during the acute phase. The glycolytic pathway was upregulated in AESD. Myristoylated alanine-rich C kinase substrate (MARCKS) and Golgi membrane protein 1 (GOLM1) were selected for validation using ELISA. Both proteins were upregulated during the acute phase (n = 11) compared with the convalescent phase (n = 21) in AESD (MARCKS, P = .016; GOLM1, P < .001). MARCKS during the acute phase was also upregulated in AESD compared with that in uncomplicated ES (n = 15) (P = .015). In CSF, 38 proteins were differentially expressed between AESD and cFS during the acute phase. Cholesteryl ester transfer protein in the CSF of patients with AESD was upregulated; however, this could not be validated using ELISA. CONCLUSIONS: Glycolysis and MARCKS pathways might be involved in HHV-6B-associated AESD pathogenesis.

ABSTRACT Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE‐HS) is an intractable form of epilepsy involving the hippocampus, and temporal lobectomy remains an effective treatment. Human herpesvirus 6B (HHV‐6B) establishes latency in the hippocampus and may contribute to MTLE‐HS pathogenesis by altering host gene expression; however, transcriptomic data from healthy controls remain limited. This study investigated the role of HHV‐6B to MTLE‐HS pathogenesis by analyzing gene expression in resected hippocampal tissues. Samples were collected from 12 to 43 HHV‐6 DNA‐positive and ‐negative patients, respectively, and three controls. RNA sequencing was performed on eight representative samples, followed by RT‐qPCR validation of nine selected genes in 58 samples. RNA sequencing identified 600 differentially expressed genes (210 upregulated, 390 downregulated) between HHV‐6B‐positive MTLE‐HS and controls. Pathway enrichment analysis revealed involvement of synaptic signaling and inflammatory responses, with prostaglandin biosynthesis specifically upregulated in HHV‐6B‐positive tissues. Two genes were significantly upregulated in HHV‐6B‐positive compared with HHV‐6B‐negative samples. RT‐qPCR confirmed elevated cholesterol 25‐hydroxylase and interleukin 1 beta expression in HHV‐6 DNA‐positive samples (both p  = 0.031). These findings suggest that HHV‐6B may contribute to MTLE‐HS pathogenesis by modulating the expression of host inflammatory genes, supporting a role for neuroinflammation and the potential benefits of anti‐inflammatory therapies.

BACKGROUND: Biliary atresia (BA) is a severe infantile hepatobiliary disorder of unknown etiology. Perinatal rotavirus (RV) infection has been implicated in animal models of BA; however, supporting human data remains limited. The study investigated the serological evidence of recent RV infection in infants with BA using RV-specific immunoglobulin (Ig)-A, a marker of primary infection unaffected by maternal antibodies. METHODS: Serum samples from 17 infants with BA and 30 age-matched controls without gastrointestinal symptoms or prior RV vaccination were retrospectively analyzed. Anti-RV-IgA titers were measured by enzyme-linked immunosorbent assay using purified WA-strain virions. Cytomegalovirus (CMV)-IgM and Epstein-Barr virus (EBV)-viral capsid antigen (VCA)-IgM levels were assessed using commercial enzyme immunoassays. RESULTS: RV-IgA was detected in 70.6% (12/17) of the patients with BA versus 3.4% (1/29) of the controls (p < 0.001). RV-IgA titers were significantly higher in the BA group (median: interquartile range 28.0:26.0-210.0) than in the control group (23.5:22.0-24.8) (p = 0.004). Among patients diagnosed with BA after 14 days of age, 84.6% (11/13) were RV-IgA-positive. CMV-IgM was detected in three patients in the BA group and one individual in the control group, while EBV-VCA-IgM was negative in BA patients and positive in two controls; neither difference was statistically significant. CONCLUSIONS: The study findings support the potential association between RV infection and BA pathogenesis. However, the lack of an epidemiological reduction in BA following the introduction of the RV vaccine warrants caution in other studies. Further prospective multicenter studies are required to elucidate the causal role of RV infection in BA development.

Abstract Heart rate variability (HRV) is a well-established, noninvasive measure of autonomic nervous system activity and is associated with clinical outcomes. Although real-time monitoring of HRV is valuable in clinical practice, its effectiveness is often compromised by major challenges: high inter-individual variability and frequent data contamination from procedural artifacts. To address these challenges, we developed and validated a computational framework for robust and personalized real-time HRV analysis oriented toward clinical application. The framework performs simultaneous analysis and visualization of both time- and frequency-domain HRV indices and incorporates an adaptive alert algorithm that personalizes alert thresholds using the interquartile range of each patient’s own data. A workflow-integrated mechanism for manually annotating and excluding artifact-prone periods prevents procedural artifacts from skewing the statistical baselines, and a multi-scale visualization module provides a unified view of short-term fluctuations and long-term trends. While existing HRV tools are powerful for research or offline analysis, they often lack the integration of personalized alerting and workflow-oriented artifact management needed for bedside care. The proposed system uniquely combines personalized alerting, care-linked artifact exclusion, and multi-scale bedside visualization within a single real-time software package. The framework was validated using open-access electrocardiogram (ECG) databases and synthetic noise-contaminated signals, confirming robust R-wave detection across pediatric and adult recordings and under low signal-to-noise conditions. In addition, the framework was operationally validated at the bedside using ECG data from 24 newborn patients. By systematically addressing the core challenges of personalization and artifact management in a clinically integrated manner, this work represents a significant step toward translating real-time HRV analysis into routine vital sign management and, ultimately, improved patient outcomes.

BACKGROUND: Buckwheat allergy carries a high risk of anaphylaxis. Although the oral food challenge (OFC) is the diagnostic gold standard, it can provoke severe reactions, leading many patients to adopt elimination diets. Conventional markers, including buckwheat-specific IgE (Bw-sIgE) and skin prick testing, have limited accuracy. The IgE crosslinking-induced luciferase expression (EXiLE) assay is a serum-based in vitro cell-activation test that has shown high accuracy for other food allergies. We evaluated its utility for buckwheat allergy. METHODS: This multicenter observational study in Japan enrolled participants with buckwheat-specific IgE ≥ 0.35 UA/mL (n = 25), categorized as buckwheat allergy (BwA) or non-buckwheat allergy (non-BwA) based on OFC results. The EXiLE assay used crude buckwheat antigen at 0.1-1000 ng/mL. Diagnostic performance was compared using receiver operating characteristic (ROC) curves for EXiLE, Bw-sIgE, and the Bw-sIgE/total IgE ratio. RESULTS: Among 25 participants, the EXiLE assay demonstrated superior diagnostic performance compared to Bw-sIgE and the Bw-sIgE/total IgE ratio. The area under the ROC curve (AUC) was 0.96 at 10 ng/mL (1 ng/mL, 0.94), exceeding Bw-sIgE (0.68) and the Bw-sIgE/total IgE ratio (0.72). At optimal cutoffs, EXiLE achieved sensitivity 0.92, specificity 0.92, and LR+ 11.1 (versus LR+ 3.2 for Bw-sIgE and 2.5 for the IgE ratio), indicating fewer false positives and better overall accuracy. CONCLUSION: The EXiLE assay provides high diagnostic accuracy for IgE-mediated buckwheat allergy and, as a serum-based in vitro assay, may reduce reliance on OFC and help avoid unnecessary elimination diets.

Human herpesviruses (HHVs) cause central nervous system (CNS) infections; however, the role of neural autoantibodies remains unclear. We aimed to assess the presence of anti-N-methyl-D-aspartate receptor (anti-NMDAR) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in HHV-associated CNS infections. Seventeen adults with HHV DNA in the cerebrospinal fluid were tested using flow cytometry-based assays. None of the patients tested positive for anti-NMDAR antibodies. Anti-MOG antibodies were detected in two patients with VZV-associated CNS infection, one appearing after deterioration and the other at onset. Both patients recovered without sequelae. Anti-MOG antibodies may arise in VZV-associated CNS infections, warranting the consideration of autoimmune mechanisms.

Varicella-zoster virus (VZV) causes varicella in children, establishes lifelong latency and reactivates to cause herpes zoster later in life. Implementation of routine varicella vaccination in Japan since 2014 has reduced varicella cases, however, breakthrough varicella still occurs. This study aimed to clarify the current distribution of VZV clade among pediatric varicella patients and adults with VZV-associated central nervous system (CNS) infections in Japan. Skin swabs were collected from varicella patients (< 15 years) in Aichi Prefecture (September 2015-August 2017). Cerebrospinal fluid (CSF) samples were obtained from adult patients (> 15 years) with VZV-associated CNS infections (November 2014-June 2023). VZV DNA was detected by PCR, and its clade was determined by sequencing open reading frame (ORF) 22 and ORF37 regions. Wild-type and Oka vaccine strains were distinguished by loop-mediated isothermal amplification (LAMP) method. Of 124 pediatric swab samples and 62 adult CSF samples 94.4% belonged to clade 2 and 4.8% clade 1. No clade 1 samples were detected in CSF samples. No vaccine strain was detected. Clinical characteristics did not differ significantly among clades. Clade 2 VZV predominates in both pediatric varicella and adult VZV-related CNS infections in Japan with sporadic clade 1 varicella cases.

UNLABELLED: As an alternative to implantable cardioverter defibrillators, the wearable cardioverter defibrillator (WCD; LifeVest®, Asahi KASEI Zoll Medical Co., Tokyo, Japan) is the only noninvasive cardioverter defibrillator available that can be worn directly on the skin. The first consensus statement on WCD use in Japan was published in 2014, and, similar to guidelines in other countries, its recommendations focus on adult patients. Pediatric cases involving WCD remain limited, and appropriate indications for its use in children are yet to be established. Here, we report the first pediatric case in Japan where WCD monitored a patient and delivered an appropriate shock to terminate a life-threatening ventricular tachycardia and ventricular fibrillation episode. During this time, the patient was recovering from takotsubo cardiomyopathy, presumably associated with refeeding syndrome secondary to Crohn's disease. No inappropriate shocks were delivered during the three-month monitoring period, and the WCD use was deemed safe. The continuous monitoring function of WCD aided in understanding the patient's conditions. Following treatment, the patient has recovered from Crohn's disease and his cardiac function has stabilized, and he has not experienced neurological sequelae or heart failure symptoms since. This case highlights the potential of WCD use in pediatric patients. LEARNING OBJECTIVE: The wearable cardioverter defibrillator (WCD; LifeVest®) is the only noninvasive cardioverter defibrillator available. However, current guidelines around the world primarily focus on adult patients. Cases of pediatric patients who are rescued by an appropriate shock by WCD are still limited and many aspects, such as device set-up, effectiveness, and risks require further study. This case supports that WCD in children can be safe and effective, demonstrating its potential to protect against ventricular tachycardia and ventricular fibrillation and prevent sudden cardiac death.

UNLABELLED: Propionic acidemia (PA) is a known cause of secondary dilated cardiomyopathy (DCM). However, little is known about how diet and heart failure treatment impact long-term cardiac outcomes in adult PA patients. We report the successful treatment of metabolic disease and secondary DCM-associated heart failure in a 20-year-old male patient with neonatal-onset PA and intellectual disability. At age 19 years, echocardiography had revealed DCM without impaired cardiac contractility. At age 20 years, he developed heart failure, presumably from a common cold infection, and was hospitalized. Acute heart failure treatment improved his symptoms, leading to discharge, but they worsened again, necessitating re-admission. He then was discharged only after successfully adding carvedilol and pimobendan to his medication. Six weeks later, however, he developed hyperammonemia with elevated serum propionyl carnitine and decreased free carnitine levels. He received acute phase treatment for this metabolic crisis and his diet therapy was readjusted, including by reducing natural protein. In the following 5 years, while continuing and slightly adapting heart failure medication and dietary regimens, the patient's cardiac function stably improved and his diuretic dose could be reduced. Our findings support that careful diet therapy and modulation of heart failure medication can improve cardiac function in PA patients with DCM. LEARNING OBJECTIVE: Neonatal-onset propionic acidemia (PA) tends to be the most severe form of PA and life-threatening metabolic disease. Even if the impact of the disease can be ameliorated by adapting the diet, later in life these patients often develop symptoms such as intellectual disability, metabolic crises, and dilated cardiomyopathy (DCM), as observed in this case. This case demonstrates that heart failure medication and dietary therapy can help protect against metabolic disease and DCM-associated heart failure in an adult patient with neonatal-onset PA.

BACKGROUND: Kawasaki disease (KD) onset has been suggested to be associated with infections and various environmental factors. However, research on whether the delivery type plays a role in KD development is limited. This study investigated whether cesarean section (CS) or vaginal delivery (VD) is associated with KD onset using a large administrative claims database in Japan. METHOD: We conducted a case-control study using the JMDC Claims Database from January 2005 to December 2021. Data on children born via CS or VD and their mothers were collected. KD patients were identified from the source population, and controls without KD were randomly selected based on sex, age and registration time, each matched to 4 controls using a risk-set sampling technique. We analyzed the association between delivery type and KD onset using multivariate conditional logistic regression, defining KD as the primary outcome based on specific criteria. RESULTS: Case-control matching created 3363 pairs of cases (n = 3363) and controls (n = 13,363). The proportions of CS, maternal age, Charlson Comorbidity Index, presence of older siblings and low birth weight infants were significantly different between the cases and controls. In the multivariate analysis, KD onset was associated with CS [odds ratio (OR): 1.12; 95% confidence interval (CI): 1.02-1.24], the presence of older siblings (OR: 1.11; 95% CI: 1.02-1.21), lower birth weight (1001-2500 g) (OR: 1.22; 95% CI: 1.04-1.43) and antibiotic use (OR: 1.12; 95% CI: 1.02-1.24). CONCLUSIONS: The risk of developing KD may be influenced by the delivery type (CS or VD), the presence of older siblings, low birth weight and antibiotic use.

Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called "endogenous HHV-6A/B (eHHV-6A/B)." Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using "eHHV-6A/B" for inherited forms and reserving "chromosomally integrated" for somatic integrations only.

The 12th International Conference on Human Herpesvirus (HHV)-6A, HHV-6B, and HHV-7 was held in Himeji, Japan, from March 25 to March 27, 2025. It attracted over 120 basic, translational, and clinical scientists from 17 countries. Important new information was presented regarding: studies of viral genes and proteins; mechanism of chromosomal integration of the viral genome; host cell interactions; inherited chromosomally integrated HHV-6A/B, also called endogenous HHV-6A/B); the role of the viruses in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS); the role of the viruses as opportunistic pathogens in immunocompromised people; the role of the viruses in diseases of the central nervous system, particularly encephalopathy, post-COVID neurological conditions, complex febrile seizures, and synucleinopathies; and the possible role of the viruses in non-Hodgkin lymphoma and autoimmune diseases, including systemic lupus erythematosus. In this review, we summarize many of the oral presentations. The full text of the Conference Abstracts is available at: https://hhv-6foundation.org/wp-content/uploads/2025/06/Abstracts_FINAL-3.10.25.pdf.

BACKGROUND: Pediatric acute hepatitis of unknown etiology (AHUE) has been reported globally since April 2022. The purpose of the present study was to investigate the impact of coronavirus disease 2019 (COVID-19) pandemic on the incidence of AHUE in Japan. METHODS: A nationwide survey of AHUE was conducted in 2510 pediatric hospitals by the Japan Pediatric Society. We retrospectively reviewed AHUE cases, defined by the World Health Organization's working case definition, and compared the incidence, clinical characteristics, and causative pathogens before the COVID-19 pandemic period (pre-pandemic, January 2017 to December 2019) and during the pandemic period (pandemic, January 2020 to June 2022). RESULTS: In total, 707 cases (450 pre-pandemic, 257 pandemic) were reported. The median age was 3 years (interquartile range (IQR): 1-9 years), and 43.8% were female. The number of AHUE cases decreased significantly in the pandemic period (102.8 cases/year) compared with the pre-pandemic period (150.0 cases/year). Investigations of pathogens causing AHUE demonstrated that the most common cause was unknown, accounting for 64% and 75% of cases in the pre-pandemic and pandemic periods, respectively. Among those whose pathogens were identified, the most common pathogens were Epstein-Barr virus (9.6%), cytomegalovirus (6.2%), and influenza (4.0%) in the pre-pandemic, and 7.0%, 3.5%, and 0.4%, respectively, in the pandemic period. SARS-CoV-2 and adenovirus were only 2.7% and 1.9%, respectively, in the pandemic period. CONCLUSIONS: The number of AHUE cases decreased during the COVID-19 pandemic compared with the pre-pandemic period, and no increase in adenovirus-associated disease or severe cases was observed in Japan.

BACKGROUND: Recent studies have reported the possible link between adeno-associated virus 2 (AAV2) and severe pediatric acute hepatitis. It has been suggested that aberrant AAV2 replication initiated by coinfection with "helper viruses" such as human adenovirus and human herpesvirus-6B (HHV-6B) may induce abnormal immune responses. Encephalitis/encephalopathy is a severe complication of primary HHV-6B infection, but the underlying mechanisms remain unclear. This study analyzed the association between AAV2 coinfection and neurologic complications of primary HHV-6B infection in children. METHODS: Preserved serum samples obtained from 36 patients with HHV-6B-associated encephalitis/encephalopathy, 39 with febrile seizure, and 83 without neurologic complications were retrospectively analyzed. Primary HHV-6B infection was confirmed if HHV-6B DNA was detected and the HHV-6B antibody was negative in serum. AAV2 and HHV-6 DNA loads were quantitated using real-time PCR. RESULTS: AAV2 was detected in 4 (11%) and 3 (8%) patients in the encephalitis/encephalopathy and febrile seizure groups, respectively. In contrast, AAV2 was undetectable in 83 patients without neurologic complications. AAV2 detection frequency was significantly higher in the encephalitis/encephalopathy and febrile seizure groups compared with the no neurologic complications group (P = 0.01 and P = 0.03, respectively). Among 4 patients with HHV-6B-associated encephalitis/encephalopathy, AAV2 DNA was detected in the cerebrospinal fluid of 2 patients. Serum HHV-6B DNA load was not significantly different among patients who were AAV2 positive or AAV negative and with or without neurologic complications. CONCLUSIONS: These findings suggest that coinfection of AAV2 and HHV-6B is associated with neurologic complications such as encephalitis/encephalopathy and febrile seizure in children.