Publications by authors named "Jun-Ichi Kawada"

68 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

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

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

Design of a prospective multicenter randomized controlled trial evaluating the effects of gastric lavage on coffee-ground emesis in neonates: study protocol.

Nagoya J Med Sci 2019 May;81(2):227-232

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

Neonates who swallow a considerable amount of maternal blood may exhibit vomiting and suckling disorder during the first few days of the postnatal period. Some clinicians treat these neonates with gastric lavage (GL) to prevent vomiting and the establishment of enteral feeding empirically, but there was no study assessing the effect of GL for neonates with coffee-ground emesis. We designed a multicenter randomized controlled trial to evaluate the efficacy and safety of GL in neonates with coffee-ground emesis. Vigorous neonates with birth weight ranging from 2500 g to 3999 g and gestational age between 37w0d and 41w6d who presented with coffee-ground emesis on more than twice and diagnosed as false melena, were divided into two groups using computerized randomization. We defined feeding intolerance (FI) as (1) ≥2 vomiting episodes in 4h or ≥3 episodes in 24h and/or (2) feeding failure on at least two occasions because of retching or poor sucking. Primary outcome is percentage of infants who present FI within 24 hours from admission. We also assessed the residual volumes, number of vomiting episodes, percentage of weight reduction at postnatal day 4, rates of body weight gain at 1 month of age, and peak serum total bilirubin value before discharge. To our knowledge, this is the first study to evaluate the safety and efficacy of GL for neonates with coffee-ground emesis. This trial is registered at UMIN Clinical Trials Registry as UMIN000026483.
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http://dx.doi.org/10.18999/nagjms.81.2.227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556448PMC
May 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

Comparison of Clinical Characteristics of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Young Children.

Jpn J Infect Dis 2019 Jul 28;72(4):237-242. Epub 2019 Feb 28.

Department of Pediatrics, Nagoya University Graduate School of Medicine.

Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory tract infection in children, and clinical manifestations of these virus infections are considered similar. To investigate the differences in clinical characteristics between HMPV and RSV infections in young children, we prospectively enrolled children < 3 years old who required hospitalization with acute respiratory tract infection due to HMPV or RSV at 10 hospitals in Japan. We enrolled 48 children with HMPV infection and 141 with RSV infection. Patients with HMPV infection were older than those with RSV infection. High-grade fever was more frequently observed in patients with HMPV infection, whereas no significant differences in respiratory symptoms were apparent. Abnormal serum lactate dehydrogenase values and consolidation shadows on chest X-ray were more frequently observed in patients with HMPV infection. During hospitalization, nasal mucus suction was more frequently required in patients with RSV infection. On the other hand, β2-adrenergic agonists, corticosteroids, and leukotriene receptor antagonists were more frequently used in patients with HMPV infection. These findings suggest that HMPV and RSV infections show similar respiratory symptoms, but HMPV infection is more likely to lead to the development of pneumonia, at least among hospitalized young children.
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http://dx.doi.org/10.7883/yoken.JJID.2018.480DOI Listing
July 2019

Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children.

J Infect Chemother 2019 May 2;25(5):346-350. Epub 2019 Feb 2.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan; Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Japan.

Background: Mycoplasma pneumoniae pneumonia (MPP) is generally a self-limiting disease, but it may become refractory. It is thought that refractory MPP is linked to the excessive immunologic responses of the host. Consequently, the use of adjunctive systemic corticosteroids may have beneficial effects. In this study, we compared the effects of high- and low-dose corticosteroid therapy in a pediatric population with refractory MPP.

Methods: We retrospectively collected data from 91 pediatric MPP patients treated with adjunctive systemic corticosteroids between April 2014 and October 2016. The patients were divided into the following two groups: high-dose corticosteroid group (2 mg/kg/day or more of prednisolone equivalents; n = 38) and low-dose corticosteroid group (<2 mg/kg/day; n = 53). Additionally, we compared the number of febrile days post-corticosteroid administration. We used 25 paired patients in a propensity score matching analysis to correct for confounding factors both by age and by days (from onset till corticosteroid therapy initiation).

Results: We observed that in the high-dose corticosteroid group defervescence following corticosteroid therapy initiation was achieved significantly earlier and length of hospitalization was significantly shorter (0.8 ± 1.0 vs. 1.5 ± 1.4 days and 8.2 ± 2.4 vs. 10.7 ± 2.7 days, respectively). In the propensity score matching, we observed that significant differences in the length of fever following corticosteroid therapy initiation and hospitalization were still present. Further, neither of the groups developed corticosteroid-related adverse events.

Conclusion: Our results suggest that patients with refractory MPP treated with high-dose corticosteroid could achieve defervescence earlier and have a shorter hospitalization.
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http://dx.doi.org/10.1016/j.jiac.2019.01.003DOI Listing
May 2019

Publisher Correction: Defective Epstein-Barr virus in chronic active infection and haematological malignancy.

Nat Microbiol 2019 Mar;4(3):544

Center for Stem Cell and Regenerative Medicine, Division of Advanced Biomedical Engineering Research, Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.

In the version of this Letter originally published, in the sentence beginning "The major driver role of DDX3X mutations...", the citation "Fig. 2a-f" should have been "Fig. 2". In addition, in the sentence beginning "Another finding of interest was the presence of identical driver mutations...", the citation "Fig. 3a,b and Fig. 4" should have been "Fig. 3". This has now been amended in all versions of the Letter.
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http://dx.doi.org/10.1038/s41564-019-0387-8DOI Listing
March 2019

Defective Epstein-Barr virus in chronic active infection and haematological malignancy.

Nat Microbiol 2019 03 21;4(3):404-413. Epub 2019 Jan 21.

Center for Stem Cell and Regenerative Medicine, Division of Advanced Biomedical Engineering Research, Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.
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http://dx.doi.org/10.1038/s41564-018-0334-0DOI Listing
March 2019

Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection.

PLoS One 2018 21;13(12):e0209595. Epub 2018 Dec 21.

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

Objective: Urinary tract infection (UTI), one of the most common bacterial infections occurring during infancy and early childhood, is frequently associated with vesicoureteral reflux (VUR). Although several guidelines recommend performing ultrasonography as a screening test, its utility is not adequate and appropriate screening tests are strongly desirable. In this study, we evaluate the use of magnetic resonance imaging (MRI) as a screening test for VUR in children with UTI.

Methods: We prospectively studied 108 patients with suspected UTI between April 2014 and March 2016. UTI was diagnosed on the basis of diffusion-weighted MRI (DW-MRI) and urine culture findings. We measured ureteral dilatation using MRI in 96 patients with UTI and assessed the relationship between ureteral dilatation in MRI and VUR in 46 patients who underwent voiding cystourethrography (VCUG).

Results: Among 108 patients, 88 and 8 were diagnosed with upper and lower UTI, respectively. Among 46 patients who underwent VCUG, 23 had VUR (14 low grade and 9 high grade). Patients with ureteral dilatation detected on MRI had VUR more frequently than those without ureteral dilatation (any grades VUR, 71% vs. 32%; P = 0.02; high-grade VUR, 38% vs. 2%, P = 0.007). Overall, ureteral dilatation findings on MRI achieved sensitivity 65.2% and specificity 73.9% as a screening test for VUR. In addition, DW-MRI achieved sensitivity 100% and specificity 81.8% in the diagnosis of upper UTI.

Conclusion: These findings suggested that MRI is a valuable tool for screening of VUR as well as diagnosis of upper UTI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303055PMC
May 2019

Reactivation of human herpesviruses 6 and 7 in Kawasaki disease.

Mod Rheumatol 2019 Jul 5;29(4):651-655. Epub 2018 Sep 5.

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

Kawasaki disease (KD) is one of the most common childhood vasculitides. Some serological studies have suggested an etiological relationship between KD and human herpesvirus (HHV)-6 or HHV-7. However, primary or reactivated HHV-6 and -7 has not been fully investigated in patients with KD. Twenty-three patients with KD were prospectively enrolled in this study. Peripheral blood was collected in the acute and convalescence phases, and HHV-6 and -7 viral loads were measured by real-time PCR. In the acute phase, HHV-6 and -7 DNA was detected in 7 (30%) patients each, compared to 13 (57%) and 9 (39%) patients in the convalescence phase, respectively. HHV-6 and -7 DNA loads were significantly higher in the convalescence phase than in the acute phase. Significant increases in HHV-6 and -7 DNA loads were not observed in disease control patients. Taking into account HHV-6 and -7 serostatus, reactivation of HHV-6 and -7 was observed in 7 and 9 patients, respectively. KD patients with HHV-6 reactivation showed higher C-reactive protein levels and more frequently required steroid therapies than patients without reactivation. HHV-6 and -7 reactivation is frequent in KD patients. HHV-6 reactivation might exacerbate the severity of KD.
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http://dx.doi.org/10.1080/14397595.2018.1510758DOI Listing
July 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

A case of refractory cytomegalovirus-related thrombocytopenia that achieved complete remission without antiviral therapy.

J Infect Chemother 2018 Dec 9;24(12):995-997. Epub 2018 Jul 9.

Department of Pediatrics, TOYOTA Memorial Hospital, Japan.

Cytomegalovirus (CMV) is one of the major infectious etiologies that induce thrombocytopenia. Although immune thrombocytopenic purpura (ITP) in children is often preceded by viral infections, thrombocytopenia associated with active CMV infection is considered CMV-related thrombocytopenia (CMV-thrombocytopenia), which can be distinguished from ITP. CMV-thrombocytopenia is reported to be less responsive to standard therapies for ITP and may require antiviral therapies. We herein report a case of refractory CMV-thrombocytopenia that achieved complete remission without antiviral therapy. A 20-month-old boy presented with a 2-day history of fever and systemic petechiae. There were no abnormal findings except for an extremely low platelet count (8000/μl) on blood examinations. He was clinically diagnosed with ITP, and intravenous immunoglobulin was administered twice, but his platelet count did not increase. CMV infection was suspected serologically, and a high CMV DNA load was detected in serum by real-time quantitative polymerase chain reaction (PCR). Without antiviral treatment, the CMV DNA load decreased below the detection limit on the 11th day of admission, followed by complete remission of the thrombocytopenia. The present case suggests that spontaneous recovery of thrombocytopenia can be expected in immunocompetent patients with CMV-thrombocytopenia in whom decreased CMV DNA load is observed.
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http://dx.doi.org/10.1016/j.jiac.2018.06.004DOI Listing
December 2018

Neurological Disorders Associated with Human Alphaherpesviruses.

Authors:
Jun-Ichi Kawada

Adv Exp Med Biol 2018 ;1045:85-102

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

Herpes simplex virus (HSV) encephalitis is the most common cause of sporadic fatal encephalitis worldwide, and central nervous system (CNS) involvement is observed in approximately one-third of neonatal HSV infections . In recent years, single-gene inborn errors of innate immunity have been shown to be associated with susceptibility to HSV encephalitis . Temporal lobe abnormalities revealed by magnetic resonance imaging-the most sensitive imaging method for HSV encephalitis-are considered strong evidence for the disease. Detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction (PCR) is the gold standard for the diagnosis of HSV encephalitis and neonatal meningoencephalitis. Intravenous acyclovir for 14-21 days is the standard treatment in HSV encephalitis. Neurological outcomes in neonates are improved by intravenous high-dose acyclovir for 21 days followed by oral acyclovir suppressive therapy for 6 months. Varicella-zoster virus (VZV) causes a wide range of CNS manifestations. VZV encephalitis typically occurs after primary infection, and reactivation of VZV may cause encephalitis. On the other hand, VZV infection of cerebral arteries produces vasculopathy, which can manifest as ischemic stroke. Vasculopathy can occur after primary infection or reactivation of VZV. PCR detection of VZV DNA in the cerebrospinal fluid can be used for the diagnosis of encephalitis or vasculopathy. Although there are no controlled treatment trials to assess VZV treatments of encephalitis or vasculopathy, intravenous acyclovir is a common treatment.
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http://dx.doi.org/10.1007/978-981-10-7230-7_5DOI Listing
November 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

Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial.

PLoS One 2018 13;13(2):e0192688. Epub 2018 Feb 13.

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

Objective: The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma.

Methods: An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment.

Results: Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group.

Conclusions: This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192688PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811027PMC
April 2018

Survey of rotavirus-associated severe complications in Aichi Prefecture.

Pediatr Int 2018 Mar;60(3):259-263

Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Background: Rotavirus can, rarely, cause severe complications such as encephalopathy/encephalitis, myocarditis, sudden death, urinary stone, and gastrointestinal (GI) bleeding; and the incidence of these severe complications remains unclear. Additionally, it has not been determined whether rotavirus (RV) vaccine could reduce cases of severe complications or not.

Methods: A two-part questionnaire was designed to determine the number and clinical features of severe complications between 1 September 2008 and 31 August 2015, including the observation periods before and after RV vaccine introduction in Aichi Prefecture.

Results: Twenty-four cases of encephalitis/encephalopathy, eight cases of sudden death, three cases of urinary tract stone, and three cases of GI bleeding were reported during the 2008/2009 season and the 2012/2013 seasons. Although five cases of encephalitis/encephalopathy were reported, no other cases of severe complications were reported during the 2013/2014 and 2014/2015 seasons. No age difference was noted according to type of complication. Although onset of encephalitis/encephalopathy and of sudden death was around day 2 of illness, that of urinary tract stone and GI bleeding was slightly later (day 6 and day 4). In addition to the eight sudden deaths, fatal outcome was also noted in four cases (13.8%) of encephalitis/encephalopathy, and in one case of GI bleeding.

Conclusion: According to the questionnaire survey in Aichi Prefecture, the incidence of the four severe RV-associated complications appears to have declined as the vaccination rate has increased.
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http://dx.doi.org/10.1111/ped.13506DOI Listing
March 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

Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schönlein purpura).

Nagoya J Med Sci 2016 Dec;78(4):359-368

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

Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch-Schönlein purpura, HSP). An abnormal urinalysis on day 7 (7d-UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA ( < 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90-0.97) and 0.98 (95% CI, 0.95-0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3-275, = 1.89 × 10). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study.
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http://dx.doi.org/10.18999/nagjms.78.4.359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159461PMC
December 2016

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

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

Diagnostic values for the viral load in peripheral blood mononuclear cells of patients with chronic active Epstein-Barr virus disease.

J Infect Chemother 2016 Apr 17;22(4):268-71. Epub 2015 Dec 17.

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

Chronic active Epstein-Barr virus disease (CAEBV) is a distinct EBV-associated lymphoproliferative disease with a poor prognosis. Although the viral load in blood samples has been widely used for diagnosing CAEBV, well-defined viral load thresholds to guide clinicians are currently lacking. The aim of the present study was to determine standardized diagnostic values for EBV load in blood samples of CAEBV patients using the World Health Organization international standard for reporting. Levels of EBV DNA in 103 peripheral blood mononuclear cells (PBMCs) and 95 plasma/serum samples from 107 cases with CAEBV were quantified and expressed in international units. Receiver operating characteristic curves were analyzed to assess the most appropriate cut-off values for levels of EBV DNA to distinguish CAEBV from EBV-associated infectious mononucleosis (IM) and controls with past EBV infection. Levels of EBV DNA in PBMCs were significantly higher in the CAEBV group (median, 10(4.2) IU/μgDNA) compared to the IM (median, 10(2.1) IU/μgDNA) and control groups. An inconsistent qualitative result was seen in 13 of 86 CAEBV patients; in these, EBV-DNA was positive in PBMCs, but negative in plasma. Diagnostic cut-off values for viral load in PBMCs from CAEBV patients, as compared to those of healthy controls and IM patients, were 10(2.0) IU/μgDNA and 10(3.2) IU/μgDNA, respectively. For diagnostic purposes, the viral load of PBMCs was better than of plasma/serum. A diagnostic cut-off EBV load for CAEBV may be useful for the management of CAEBV patients.
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http://dx.doi.org/10.1016/j.jiac.2015.11.002DOI Listing
April 2016
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