Publications by authors named "Yuka Torii"

37 Publications

Pediatric sepsis cases diagnosed with group B streptococcal meningitis using next-generation sequencing: a report of two cases.

BMC Infect Dis 2021 Jun 5;21(1):531. Epub 2021 Jun 5.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Group B Streptococcus (GBS) is an important cause of invasive infection in neonates and infants. Cerebrospinal fluid (CSF) findings and culture may not show evidence of infection early in GBS meningitis. Next-generation sequencing (NGS) has the potential to detect microbial genetic material in patients with infectious diseases. We report two cases of infantile sepsis of GBS meningitis with negative results for CSF culture tests, but positive results for NGS analysis.

Case Presentation: Patient 1 was a 22-day-old male infant diagnosed with sepsis and meningitis. His CSF findings showed pleocytosis, decreased glucose, and increased protein levels. However, CSF and blood culture results at admission were negative. He received a total of 3 weeks of treatment with ampicillin and cefotaxime, and showed clinical improvement. GBS was detected through NGS analysis of CSF collected at admission. Patient 2 was a 51-day-old male infant with sepsis. CSF findings on admission were normal, and blood and CSF cultures were also negative. Intravenous ampicillin and cefotaxime treatment were initiated. Treatment was de-escalated to ampicillin alone because Enterococcus faecalis was cultured from urine. He was discharged after a total of 1 week of antibiotic treatment. Six days after discharge, he was re-hospitalized for sepsis. Blood and CSF cultures were negative, and E. faecalis was again cultured from urine. He received a total of 3 weeks of ampicillin treatment for enterococcal-induced nephritis and did not relapse thereafter. NGS pathogen searches were retrospectively performed on both blood and CSF collected at the first and second admission. GBS was detected in the CSF collected at the first admission, but no significant pathogen was detected in the other samples. Inadequate treatment for GBS meningitis at the first admission may have caused the recurrence of the disease.

Conclusion: Infantile sepsis may present bacterial meningitis that is not diagnosed by either culture testing or CSF findings. NGS analysis for CSF may be useful for confirming the diagnosis of bacterial meningitis.
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http://dx.doi.org/10.1186/s12879-021-06231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180162PMC
June 2021

A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature.

J Med Case Rep 2021 May 25;15(1):285. Epub 2021 May 25.

Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5-8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia.

Case Presentation: A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment.

Conclusion: This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.
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http://dx.doi.org/10.1186/s13256-021-02885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146239PMC
May 2021

Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study.

BMC Microbiol 2021 Apr 6;21(1):104. Epub 2021 Apr 6.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events.

Results: In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition.

Conclusions: The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.
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http://dx.doi.org/10.1186/s12866-021-02154-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025517PMC
April 2021

MRI findings in children with congenital cytomegalovirus infection retrospectively diagnosed with dried umbilical cord.

Neuroradiology 2021 May 17;63(5):761-768. Epub 2020 Nov 17.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.

Purpose: Brain MRI provides important information about suspected congenital CMV infection in neonatally underdiagnosed children. This study aimed to describe MRI findings in children in whom congenital CMV infection was not suspected during the neonatal period and was proven retrospectively.

Methods: We enrolled 31 children referred to the pediatric neurology clinic with neurological symptoms who were proven to have congenital CMV infection based on dried umbilical cord samples. Upon diagnosis, MR and CT images were assessed using the van der Knaap scoring system integrated with additional variables. Two investigators independently assessed all images.

Results: The age at diagnosis was < 12 months in 14, 12-24 months in 11, and > 24 months in 6 patients. The initial symptom triggering clinic referral was delayed development in 22, seizure in 5, deafness in 3, and hemiplegia in 1 patient. Of the 31 children, 30 had a white matter (WM) abnormality predominant in the deep WM of the parietal lobe (n = 25). Anterior temporal lesions were observed in 21 children. Cortical lesions were observed in 7 children, suggestive of polymicrogyria. No child had cerebellar or brainstem abnormalities. Brain CT was performed in 22 of 31 children, and 11 showed punctate cerebral calcification in the periventricular and/or deep WM.

Conclusion: Patients with congenital CMV infection with delayed neurological symptoms show a relatively uniform pattern of parietal-dominant multifocal WM lesions and anterior temporal lesions, with or without polymicrogyria.
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http://dx.doi.org/10.1007/s00234-020-02603-9DOI Listing
May 2021

Comprehensive pathogen detection in sera of Kawasaki disease patients by high-throughput sequencing: a retrospective exploratory study.

BMC Pediatr 2020 10 15;20(1):482. Epub 2020 Oct 15.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Kawasaki disease (KD) is an idiopathic systemic vasculitis that predominantly damages coronary arteries in children. Various pathogens have been investigated as triggers for KD, but no definitive causative pathogen has been determined. As KD is diagnosed by symptoms, several days are needed for diagnosis. Therefore, at the time of diagnosis of KD, the pathogen of the trigger may already be diminished. The aim of this study was to explore comprehensive pathogens in the sera at the acute stage of KD using high-throughput sequencing (HTS).

Methods: Sera of 12 patients at an extremely early stage of KD and 12 controls were investigated. DNA and RNA sequences were read separately using HTS. Sequence data were imported into the home-brew meta-genomic analysis pipeline, PATHDET, to identify the pathogen sequences.

Results: No RNA virus reads were detected in any KD case except for that of equine infectious anemia, which is known as a contaminant of commercial reverse transcriptase. Concerning DNA viruses, human herpesvirus 6B (HHV-6B, two cases) and Anelloviridae (eight cases) were detected among KD cases as well as controls. Multiple bacterial reads were obtained from KD and controls. Bacteria of the genera Acinetobacter, Pseudomonas, Delfita, Roseomonas, and Rhodocyclaceae appeared to be more common in KD sera than in the controls.

Conclusion: No single pathogen was identified in serum samples of patients at the acute phase of KD. With multiple bacteria detected in the serum samples, it is difficult to exclude the possibility of contamination; however, it is possible that these bacteria might stimulate the immune system and induce KD.
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http://dx.doi.org/10.1186/s12887-020-02380-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557310PMC
October 2020

Comprehensive Detection of Candidate Pathogens in the Lower Respiratory Tract of Pediatric Patients With Unexpected Cardiopulmonary Deterioration Using Next-Generation Sequencing.

Pediatr Crit Care Med 2020 11;21(11):e1026-e1030

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: Next-generation sequencing has been applied to the investigation of microorganisms in several clinical settings. We investigated the infectious etiologies in respiratory specimens from pediatric patients with unexpected cardiopulmonary deterioration using next-generation sequencing.

Design: Retrospective, single-center, observational study.

Setting: Tertiary care, a children's hospital.

Subjects: The study enrolled a total of 16 pediatric patients with unexpected cardiopulmonary deterioration who were admitted to the PICU. Ten bronchoalveolar lavage fluid and six transtracheal aspirate samples were analyzed.

Interventions: None.

Measurements And Main Results: RNA libraries were prepared from specimens and analyzed using next-generation sequencing. One or more bacterial/viral pathogens were detected in the bronchoalveolar lavage fluid or transtracheal aspirate specimens from 10 patients. Bacterial and viral coinfection was considered in four cases. Compared with the conventional culture and viral antigen test results, an additional six bacterial and four viral pathogens were identified by next-generation sequencing. Conversely, among 18 pathogens identified by the conventional methods, nine pathogens were detected by next-generation sequencing. Candidate pathogens (e.g., coxsackievirus A6 and Chlamydia trachomatis) were detected by next-generation sequencing in four of 10 patients in whom no causative pathogen had been identified by conventional methods.

Conclusions: Our results suggest that viral and bacterial infections are common triggers in unexpected cardiopulmonary deterioration in pediatric patients. Next-generation sequencing has the potential to contribute to clarification of the etiology of pediatric critical illness.
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http://dx.doi.org/10.1097/PCC.0000000000002558DOI Listing
November 2020

Immune cell infiltration landscapes in pediatric acute myocarditis analyzed by CIBERSORT.

J Cardiol 2021 02 3;77(2):174-178. Epub 2020 Sep 3.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Myocarditis is an inflammatory disease of the myocardium, which leads to cardiac dysfunction and heart failure. Previous studies have suggested that complex cross-talk between innate and adaptive immune responses is involved in the pathogenesis of acute myocarditis. Immunohistochemistry is the current standard method for the evaluation of infiltrating immune cells, however, it is difficult to investigate and quantify many immune cell populations using this technique.

Methods: Endomyocardial biopsy samples of five pediatric patients with myocarditis were analyzed by cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT), a computational method for quantifying cell fractions from tissue gene expression profiles. CIBERSORT results were then compared with immunohistochemistry analyses.

Results: Significant results of immune infiltrate deconvolution were obtained in four patients with fulminant myocarditis by CIBERSORT analysis. Among 22 immune cell types, 19 cell types were detected in one or more patients. Activated NK cells were the most prevalent population in two patients, whereas activated memory CD4 T cells and M2 macrophages were the most prevalent population in one patient each. Overall CIBERSORT results were consistent with those of immunohistochemistry, although some discrepancies were observed.

Conclusions: Infiltrating immune cell subsets detected by CIBERSORT analysis can reflect the time course of innate and adaptive immune responses in acute myocarditis. CIBERSORT may have the potential to characterize the detail of infiltrating immune cells in myocardial tissues and provide novel insights into the pathogenesis of acute myocarditis.
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http://dx.doi.org/10.1016/j.jjcc.2020.08.004DOI Listing
February 2021

Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study.

Bone Marrow Transplant 2020 09 20;55(9):1872-1874. Epub 2020 Mar 20.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

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http://dx.doi.org/10.1038/s41409-020-0867-8DOI Listing
September 2020

Metagenomic analysis using next-generation sequencing of pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure.

Sci Rep 2019 09 9;9(1):12909. Epub 2019 Sep 9.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Next-generation sequencing (NGS) has been applied in the field of infectious diseases. Bronchoalveolar lavage fluid (BALF) is considered a sterile type of specimen that is suitable for detecting pathogens of respiratory infections. The aim of this study was to comprehensively identify causative pathogens using NGS in BALF samples from immunocompetent pediatric patients with respiratory failure. Ten patients hospitalized with respiratory failure were included. BALF samples obtained in the acute phase were used to prepare DNA- and RNA-sequencing libraries. The libraries were sequenced on MiSeq, and the sequence data were analyzed using metagenome analysis tools. A mean of 2,041,216 total reads were sequenced for each library. Significant bacterial or viral sequencing reads were detected in eight of the 10 patients. Furthermore, candidate pathogens were detected in three patients in whom etiologic agents were not identified by conventional methods. The complete genome of enterovirus D68 was identified in two patients, and phylogenetic analysis suggested that both strains belong to subclade B3, which is an epidemic strain that has spread worldwide in recent years. Our results suggest that NGS can be applied for comprehensive molecular diagnostics as well as surveillance of pathogens in BALF from patients with respiratory infection.
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http://dx.doi.org/10.1038/s41598-019-49372-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733840PMC
September 2019

Viral DNA Loads in Various Blood Components of Patients With Epstein-Barr Virus-Positive T-Cell/Natural Killer Cell Lymphoproliferative Diseases.

J Infect Dis 2019 09;220(8):1307-1311

Department of Pediatrics, Nagoya University Graduate School of Medicine, Tokyo, Japan.

To evaluate diagnostic values for Epstein-Barr virus (EBV) DNA loads in different blood components of patients with EBV-positive T-cell/natural killer cell lymphoproliferative diseases, EBV DNA loads were compared among disease categories in each blood component from 59 patients. Plasma viral loads were significantly higher in "active" disease in chronic active EBV infection. EBV DNA was not detected in the plasma from 7 patients in whom EBV DNA was detected in peripheral blood mononuclear cells and whole blood. Diagnostic cutoff values for whole blood EBV DNA loads of patients with chronic active EBV infection compared with those of infectious mononucleosis was 104.2 (15 800) IU/mL.
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http://dx.doi.org/10.1093/infdis/jiz315DOI Listing
September 2019

Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection.

BMC Pregnancy Childbirth 2019 Jun 20;19(1):205. Epub 2019 Jun 20.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Cytomegalovirus (CMV) is one of the most frequent pathogens for congenital infections. Most cases of congenital CMV infection (cCMV) are asymptomatic at birth, but sensorineural hearing loss (SNHL) or neurodevelopmental delay can appear later in childhood. This prospective study examined the practicability of serological screening for anti-CMV immunoglobulin (Ig) G and anti-CMV IgM in pregnant women.

Methods: A total of 11,753 pregnant women were examined for CMV IgG and CMV IgM during the first or second trimester. When IgM was positive, IgG was reevaluated more than two weeks later. When IgG was negative, IgG was reevaluated in the second or third trimester. All neonates from mothers with positive/borderline IgM or IgG seroconversion underwent polymerase chain reaction assay for CMV using urine samples to diagnose cCMV. Levels of IgG and IgM were compared between mothers with and without cCMV. Receiver operating characteristic (ROC) curves for IgM titers were analyzed.

Results: Eight of 500 neonates (1.6%) born from mothers with positive IgG and positive IgM, and 3 of 13 neonates (23.1%) born from mothers with IgG seroconversion were diagnosed with cCMV. Neither IgM titers nor IgG titers differed significantly between cCMV and non-cCMV groups. The area under the ROC curve was 0.716 and the optimal cut-off for IgM was 7.28 index (sensitivity = 0.625, specificity = 0.965, positive predictive value = 0.238, negative predictive value = 0.993). Titers of IgG were not frequently elevated in pregnant women with positive IgM during the observation period, including in those with cCMV. All 11 cCMV cases were asymptomatic at birth and none had shown SNHL or developmental delay as of the last regular visit (mean age, 40 months).

Conclusions: Seroconversion of CMV IgG and high-titer IgM during early pregnancy are predictors of cCMV. High IgM titer (> 7.28 index) is a predictor despite relatively low sensitivity. Levels of IgG had already plateaued at first evaluation in mothers with cCMV. Maternal screening offered insufficient positive predictive value for diagnosing cCMV, but allowed identifying asymptomatic cCMV cases in an early stage.
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http://dx.doi.org/10.1186/s12884-019-2360-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585127PMC
June 2019

Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing.

J Med Virol 2018 12 13;90(12):1814-1821. Epub 2018 Aug 13.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Myocarditis is an inflammatory disease of the myocardium and leads to cardiac dysfunction and heart failure. Although viral infections are considered to be the most common etiology of myocarditis, the identification of the causative virus is still challenging. Recently, next-generation sequencing (NGS) has been applied in the diagnosis of infectious diseases. The aim of the current study was to comprehensively analyze potential pathogenic microorganisms using NGS in the sera of patients with myocarditis. Twelve pediatric and five adult patients hospitalized for acute myocarditis were included. Serum samples in the acute phase were obtained and analyzed using NGS to detect pathogen-derived DNA and RNA. Viral sequence reads were detected in 7 (41%) of the 17 myocarditis patients by NGS. Among these patients, detection of Epstein-Barr virus, human parvovirus B19, torque teno virus, and respiratory syncytial virus reads by NGS was consistent with polymerase chain reaction or antigen test results in one patient each. A large number of human pegivirus reads were detected from one patient by RNA sequencing; however, its pathogenicity to human is unknown. Conversely, the number of detected virus-derived reads was small in most cases, and the pathophysiological role of these viruses remains to be clarified. No significant bacterial or fungal reads other than normal bacterial flora was detected. These data indicate that comprehensive detection of virus-derived DNA and RNA using NGS can be useful for the identification of potential pathogenic viruses in myocarditis.
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http://dx.doi.org/10.1002/jmv.25263DOI Listing
December 2018

Congenital Cytomegalovirus Pneumonitis and Treatment Response Evaluation Using Viral Load during Ganciclovir Therapy: a Case Report.

Jpn J Infect Dis 2018 Jul 27;71(4):309-311. Epub 2018 Apr 27.

Department of Pediatrics, National Center for Global Health and Medicine.

Cytomegalovirus (CMV) is the most common cause of congenital infection. Pneumonitis is considered to be a rare manifestation although congenital CMV infection presents with various non-specific findings. Ganciclovir and valganciclovir are beneficial for improving neurodevelopmental sequelae and hearing outcomes of congenital CMV infection; however, treatment response evaluation is not well reported. We report a female case of congenital CMV infection presenting with pneumonitis, meningoencephalitis, and chorioretinitis. She was treated with intravenous ganciclovir for 6 weeks, and clinical features improved. Measurement of the CMV genome load by real-time polymerase chain reaction assay was performed during treatment. After the administration of ganciclovir, the CMV genome was not detected in the blood and levels decreased gradually in the urine. Physicians should consider the possibility of congenital CMV infection in neonates who present with respiratory distress. Furthermore, measurement of the CMV genome load in blood and urine may be useful for evaluating treatment response.
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http://dx.doi.org/10.7883/yoken.JJID.2017.577DOI Listing
July 2018

Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells.

Cancer Med 2018 04 9;7(4):1275-1284. Epub 2018 Mar 9.

Departments of Virology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in EBV-associated lymphomas and can be a novel therapeutic target. An oral dual inhibitor of PI3Kγ and PI3Kδ, duvelisib, is in clinical trials for the treatment of lymphoid malignancies. In this study, we evaluated how duvelisib affects the activity of the PI3K/Akt signaling pathway and if it has antitumor effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt signaling pathway was activated in most of the B and T cell lymphoma cell lines tested. Additionally, duvelisib treatment inhibited cellular growth in the tested cell lines. Overall, B cell lines were more susceptible to duvelisib than T and NK cell lines in vitro regardless of EBV infection. However, the additional influence of duvelisib on the tumor microenvironment was not assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore, duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and gp350/220) in EBV-positive B cell lines, suggesting that duvelisib suppresses the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib did not induce a remarkable change in the expression of EBV latent genes. These results may indicate that there is therapeutic potential for duvelisib administration in the treatment of EBV-associated B cell lymphomas and other B cell malignancies.
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http://dx.doi.org/10.1002/cam4.1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911584PMC
April 2018

Comprehensive detection of pathogens in immunocompromised children with bloodstream infections by next-generation sequencing.

Sci Rep 2018 02 28;8(1):3784. Epub 2018 Feb 28.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Bloodstream infection (BSI) is a severe complication in immunocompromised patients. Next-generation sequencing (NGS) allows us to analyze comprehensively and quantitatively all microorganisms present in a clinical sample. Thirty-five pediatric patients (12 with BSI and 23 with suspected BSI/negative blood culture) were enrolled. Plasma/serum samples were used for sequencing and the results were compared with those from blood culture. Sequencing reads of bacteria isolated in blood culture were identified by NGS in all plasma/serum samples at disease onset. Bacteria isolated in blood culture were identical to the dominant bacteria by NGS in 8 of 12 patients. Bacterial reads per million reads of the sequence depth (BR) > 200 and relative importance values of the dominant bacteria (P1) > 0.5 were employed to determine causative pathogens. Causative pathogens were detected using these criteria in 7 of 12 patients with BSI. Additionally, causative bacteria were detected in the plasma/serum at 7 days before disease onset in two patients with catheter-related BSI. Causative pathogens, including virus, were identified in three patients with suspected BSI. Lastly, a total of 62 resistance genes were detected by NGS. In conclusion, NGS is a new method to identify causative microorganisms in BSI and may predict BSI in some patients.
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http://dx.doi.org/10.1038/s41598-018-22133-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830625PMC
February 2018

Comprehensive detection of viruses in pediatric patients with acute liver failure using next-generation sequencing.

J Clin Virol 2017 11 3;96:67-72. Epub 2017 Oct 3.

Departments of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. Electronic address:

Background: Pediatric acute liver failure (PALF) is a rare and severe syndrome that frequently requires liver transplantation. Viruses are one of the most frequent causes of this disease, however, pathogenic viruses are not determined in many patients. Recently next-generation sequencing (NGS) has been applied to comprehensively detect pathogens of infectious diseases of unknown etiology.

Objectives: To evaluate an NGS-based approach for detecting pathogenic viruses in patients with PALF or acute hepatitis of unknown etiology.

Study Design: To detect virus-derived DNA and RNA sequences existing in sera/plasma from patients, both DNA and RNA sequencing were performed. First, we validated the ability of NGS to detect viral pathogens in clinical serum/plasma samples, and compared different commercial RNA library preparation methods Then, serum/plasma of fourteen patients with PALF or acute hepatitis of unknown etiology were evaluated using NGS.

Results: Among three RNA library preparation methods, Ovation RNA-Seq System V2 had the highest sensitivity to detect RNA viral sequences. Among fourteen patients, sequence reads of torque teno virus, adeno-associated virus, and stealth virus were found in the sera of one patient each, however, the pathophysiological role of these three viruses was not clarified. Significant virus reads were not detected in the remaining 11 patients.

Conclusions: This finding might be due to low virus titer in blood at the time of referral or a non-infectious cause might be more frequent. These results suggest an NGS-based approach has potential to detect viral pathogens in clinical samples and would contribute to clarification of the etiology of PALF.
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http://dx.doi.org/10.1016/j.jcv.2017.10.001DOI Listing
November 2017

Epstein-Barr virus infection-induced inflammasome activation in human monocytes.

PLoS One 2017 3;12(4):e0175053. Epub 2017 Apr 3.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1β (IL-1β) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1β production, while EBV infection of B-cell or T-cell lines did not induce IL-1β production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1β production, and that AIM2, acting as an inflammasome, is involved in this response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378412PMC
September 2017

Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.

Oncotarget 2016 Nov;7(47):76793-76805

Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.
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http://dx.doi.org/10.18632/oncotarget.12529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363550PMC
November 2016

Primary psoas abscess caused by group A streptococcus in a child: Case report with microbiologic findings.

J Infect Chemother 2016 Dec 28;22(12):811-814. Epub 2016 Sep 28.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Primary abscess of the iliopsoas muscle in children is uncommon, especially due to Streptococcus pyogenes (group A streptococcus: GAS), which causes a variety of diseases ranging from pharyngitis to invasive life-threatening infection. We present primary iliopsoas abscess in a nine-year-old boy presenting with fever, mild disturbance of consciousness, limp, and pain in the right loin. Magnetic resonance imaging and isolation of GAS from both blood and abscess samples led us to the confirmative diagnosis. The patient recovered after treatment comprising drainage and intravenous antibiotics. The CovRS system is one of the best-characterized systems with two-component signal transduction in the GAS, and mutations in covRS induce overproduction of various virulence factors that play a crucial role in invasive GAS infection. RopB, also known as a GAS regulator, influences the expression of multiple regulatory networks to coregulate virulence factor expression in GAS. In the present case, sequence analysis revealed the isolated GAS as emm type 6 with alterations in covS, whereas the covR and ropB genes were intact. The covS alterations might have influenced the virulence of the strain causing this severe GAS infection.
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http://dx.doi.org/10.1016/j.jiac.2016.06.011DOI Listing
December 2016

Identification of Viruses in Cases of Pediatric Acute Encephalitis and Encephalopathy Using Next-Generation Sequencing.

Sci Rep 2016 09 14;6:33452. Epub 2016 Sep 14.

Departments of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Acute encephalitis/encephalopathy is a severe neurological syndrome that is occasionally associated with viral infection. Comprehensive virus detection assays are desirable because viral pathogens have not been identified in many cases. We evaluated the utility of next-generation sequencing (NGS) for detecting viruses in clinical samples of encephalitis/encephalopathy patients. We first determined the sensitivity and quantitative performance of NGS by comparing the NGS-determined number of sequences of human herpesvirus-6 (HHV-6) in clinical serum samples with the HHV-6 load measured using real-time PCR. HHV-6 was measured as it occasionally causes neurologic disorders in children. The sensitivity of NGS for detection of HHV-6 sequences was equivalent to that of real-time PCR, and the number of HHV-6 reads was significantly correlated with HHV-6 load. Next, we investigated the ability of NGS to detect viral sequences in 18 pediatric patients with acute encephalitis/encephalopathy of unknown etiology. A large number of Coxsackievirus A9 and mumps viral sequences were detected in the cerebrospinal fluid of 2 and 1 patients, respectively. In addition, Torque teno virus and Pepper mild mottle viral sequences were detected in the sera of one patient each. These data indicate that NGS is useful for detection of causative viruses in patients with pediatric encephalitis/encephalopathy.
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http://dx.doi.org/10.1038/srep33452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022051PMC
September 2016

Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor.

Pediatr Transplant 2016 Feb 30;20(1):105-13. Epub 2015 Oct 30.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.
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http://dx.doi.org/10.1111/petr.12620DOI Listing
February 2016

Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases.

J Infect Chemother 2015 Dec 28;21(12):857-63. Epub 2015 Sep 28.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein-Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection.

Methods: Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT.

Results: The AdV DNA became detectable (1 × 10(4) copies/mL) as early as 2 weeks after HSCT. These levels reached >1 × 10(8) copies/mL at the onset of fulminant hepatitis. However, we determined that γ-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis.

Conclusions: Our observation raises the possibility that elevated γ-glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment.
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http://dx.doi.org/10.1016/j.jiac.2015.08.018DOI Listing
December 2015

Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis.

Clin Rheumatol 2015 Oct 7;34(10):1705-12. Epub 2015 Apr 7.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression of targeted mRNAs, which are important in the pathogenesis of autoimmune diseases. MiRNAs may have the potential to serve as biomarkers of disease. We evaluated serum levels of selected miRNAs and their associations with disease activity in juvenile idiopathic arthritis (JIA). Sera and peripheral blood leukocytes were collected from patients with JIA (8 systemic onset, 16 polyarthritis) and healthy controls. Levels of miR-16, miR-132, miR-146a, miR-155, and miR-223 were quantified. Levels of miR-223 in sera were significantly higher in patients in the active phase of systemic onset JIA than in controls. MiRNAs of peripheral blood leukocytes did not exhibit any difference between patients with JIA and controls. In both systemic onset JIA and polyarthritis patients, levels of miR-223 and miR-16 correlated with erythrocyte sedimentation rate and matrix metalloproteinase-3, respectively. MiR-146a and miR-223 in polyarthritis showed correlations with matrix metalloproteinase-3. Expressions of miRNAs were altered in patients with JIA. Serum levels of miR-223 may be a potential disease biomarker. Investigation of miRNAs could be helpful in understanding the pathogenesis of JIA and could aid in the identification of additional disease biomarkers.
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http://dx.doi.org/10.1007/s10067-015-2922-1DOI Listing
October 2015

Viral load in children with congenital cytomegalovirus infection identified on newborn hearing screening.

J Clin Virol 2015 Apr 23;65:41-5. Epub 2015 Jan 23.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. However, congenital SNHL without other clinical abnormalities is rarely diagnosed as CMV-related in early infancy.

Objectives: The aim of this study was to identify and treat patients with congenital CMV-related SNHL or CMV-related clinical abnormalities other than SNHL. The association between CMV load and SNHL was also evaluated.

Study Design: Newborns who had abnormal hearing screening results or other clinical abnormalities were screened for congenital CMV infection by PCR of saliva or urine specimens, and identified infected patients were treated with valganciclovir (VGCV) for 6 weeks. The CMV load of patients with or without SNHL was compared at regular intervals during as well as after VGCV treatment.

Results: Of 127 infants with abnormal hearing screening results, and 31 infants with other clinical abnormalities, CMV infection was identified in 6 and 3 infants, respectively. After VGCV treatment, 1 case had improved hearing but the other 5 SNHL cases had little or no improvement. Among these 9 patients with or without SNHL at 1 year of age, there was no significant difference in CMV blood or urine load at diagnosis, but both were significantly higher in patients with SNHL during VGCV treatment.

Conclusions: Selective CMV screening of newborns having an abnormal hearing screening result would be a reasonable strategy for identification of symptomatic congenital CMV infection. Prolonged detection of CMV in blood could be a risk factor for SNHL.
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http://dx.doi.org/10.1016/j.jcv.2015.01.015DOI Listing
April 2015

Immunogenicity of inactivated seasonal influenza vaccine in adult and pediatric liver transplant recipients over two seasons.

Microbiol Immunol 2013 Oct;57(10):715-22

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Immunological responses to influenza vaccination administered to liver transplantation recipients are not fully elucidated. To compare inactivated influenza vaccine's immunogenicity between adult and pediatric recipients, 16 adult and 15 pediatric living donor liver transplantation recipients in the 2010-11 influenza season, and 53 adult and 21 pediatric recipients in the 2011-12 season, were investigated. Seroprotection rates (hemagglutinin-inhibition [HI] antibody titer 1:40) were 50-94% to all three antigens among adults and 27-80% among children in both seasons. Seroconversion rates (fourfold or more HI antibody rise) were 32-56% among adults and 13-67% among children in both seasons. No significant differences were observed between the two groups. In addition, 20/53 adult and 13/21 pediatric recipients received a vaccine containing identical antigens in both of these seasons. Geometric mean titer fold increases of all three antigens in adult recipients were significantly lower than those in recipients who had not received a preceding vaccination. In contrast, in pediatric recipients, there were no significant differences between the groups who had and had not received preceding vaccinations. The number of patients with rejection did not differ significantly between the two groups (0/53 vs. 1/21) in the 2011-12 season. The incidence of influenza after vaccination was significantly different between adult and pediatric recipients (0/16 vs. 5/15 in 2010-11 and 0/53 vs. 3/21 in 2011-12, respectively). Overall, there were no significant differences in antibody responses between adult and pediatric groups. Influenza infection was more frequent in pediatric recipients. Long-term response to preceding vaccinations appeared to be insufficient in both groups.
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http://dx.doi.org/10.1111/1348-0421.12086DOI Listing
October 2013

Plasma viral microRNA profiles reveal potential biomarkers for chronic active Epstein-Barr virus infection.

J Infect Dis 2013 Sep 17;208(5):771-9. Epub 2013 May 17.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Chronic active Epstein-Barr virus (CAEBV) infection has high mortality and morbidity, and biomarkers for disease severity and prognosis are required. MicroRNAs (miRNAs) are small noncoding RNAs, and EBV encodes multiple miRNAs. Because plasma contains sufficiently stable miRNAs, circulating EBV-associated miRNA profiles were investigated as novel biomarkers in CAEBV infection.

Methods: Plasma miRNA expression was assessed for 12 miRNAs encoded within 2 EBV open reading frames (BART and BHRF). Expression levels were investigated in 19 patients with CAEBV infection, 14 patients with infectious mononucleosis, and 11 healthy controls. Relative expression levels of plasma miRNAs were determined by TaqMan probe-based quantitative assay.

Results: Plasma miR-BART1-5p, 2-5p, 5, and 22 levels in patients with CAEBV infection were significantly greater than those in patients with infectious mononucleosis and in controls. Plasma miR-BART2-5p, 4, 7, 13, 15, and 22 levels were significantly elevated in patients with CAEBV infection with systemic symptoms, compared with levels in patients with no systemic symptoms. The levels of miR-BART2-5p, 13, and 15 showed clinical cutoff values associated with specific clinical conditions, in contrast to plasma EBV loads.

Conclusions: Levels of specific plasma EBV miRNAs were elevated differentially in patients with CAEBV infection. Several EBV miRNAs, particularly miR-BART2-5p, 13, and 15, are potentially biomarkers of disease severity or prognosis.
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http://dx.doi.org/10.1093/infdis/jit222DOI Listing
September 2013

Risk factors for poor outcome in congenital cytomegalovirus infection and neonatal herpes on the basis of a nationwide survey in Japan.

Pediatr Int 2013 Oct 30;55(5):566-71. Epub 2013 Jul 30.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Congenital cytomegalovirus (CMV) infection and neonatal herpes are major mother-to-child infections, and analyses of the important clinical issues, including risk factors for prognosis, are essential.

Methods: A secondary survey of congenital CMV infection and neonatal herpes was performed using questionnaires for cases reported in the primary survey between 2006 and 2008.

Results: Univariate analysis of 71 cases of congenital CMV infection showed that intrauterine growth restriction (IUGR) or other specific findings on fetal ultrasonography (US), microcephaly, intracranial calcification, disseminated intravascular coagulation, abnormal findings on computed tomography, and the use of i.v. gammaglobulin were all significantly correlated with poor outcome (death or severe sequelae). Multivariate analysis showed that only IUGR was significantly associated with poor outcome. Hearing impairment is one of the major abnormalities associated with congenital CMV infection. Automatic auditory brainstem response (automatic ABR) appeared to be useful for detection of hearing impairment in comparison with conventional ABR. Moreover, univariate analysis showed that specific fetal US or abnormal magnetic resonance imaging findings were correlated with sensorineural hearing loss. In 24 cases of neonatal herpes, fever and seizure were correlated with poor outcome on univariate analysis. All patients received acyclovir treatment, although substantial numbers of patients in severe clinical categories (disseminated or central nervous system diseases) received a low dose of acyclovir (<60 mg/kg per day).

Conclusions: This secondary survey has identified the risk factors associated with outcome and important issues in diagnosis and treatment of two mother-to-child infections: congenital CMV and neonatal herpes, in Japan.
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http://dx.doi.org/10.1111/ped.12122DOI Listing
October 2013

Clinicoepidemiologic status of mother-to-child infections: a nationwide survey in Japan.

Pediatr Infect Dis J 2013 Jun;32(6):699-701

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

We conducted a nationwide survey of the present status of 10 representative mother-to-child infections in Japan. Congenital syphilis, vertical human T-cell leukemia virus type 1 infection, congenital rubella and vertical HIV infection, for which effective preventative strategies have been established, were rare. Cytomegalovirus was the most common congenital pathogen in Japan, although most infants with congenital cytomegalovirus infection may remain undiagnosed.
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http://dx.doi.org/10.1097/INF.0b013e3182897c36DOI Listing
June 2013

Causes of vertical transmission of hepatitis B virus under the at-risk prevention strategy in Japan.

Microbiol Immunol 2013 Feb;57(2):118-21

Department of Pediatrics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.

The number of hepatitis B virus (HBV) carrier babies has decreased markedly since the introduction in Japan of an "at-risk" strategy for preventing HBV infection. However, elimination of HBV infection from our country appears difficult. To clarify the limitations of the at-risk strategy for preventing vertical transmission of HBV, causes of vertical transmission in a single hospital were retrospectively analyzed. The following causes were presumed in 17 carrier pediatric cases: five patients had prenatal HBV infection, HBV infection during/after the immunization program was confirmed in five cases, two patients had prenatal infection or infection during the immunization program and three cases were caused by human error (by the patients' guardians). Because their mothers were HBV-negative at screening and only developed acute hepatitis B in the perinatal period, another two cases (Cases 3 and 10) did not undergo immunization because they were not subjects of the at-risk strategy. Sequence analyses in ten patients revealed genotype C (subgenotype, C2/Ce) in nine cases and genotype A (subgenotype, A2/Ae) in one case (Case 3). In Japan, HBV subgenotype Ae has recently been found more frequently among sexually active men with acute hepatitis. There are concerns that horizontal transmission of HBV from these men to their pregnant partners could increase. These data suggest clear limitations to the at-risk strategy in Japan and the possibility that the increase in genotype A may influence vertical transmission of HBV.
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http://dx.doi.org/10.1111/1348-0421.12009DOI Listing
February 2013