Faculty Profiles - TORII Yuka

Papers - TORII Yuka

Division display >> ／ All the affair displays 1 - 73 of about 73

Single-cell transcriptomics reveal heat shock protein dysregulation in severe SARS-CoV-2-associated pediatric encephalopathy Invited Reviewed Open Access

2026.3

Survey of Attitudes Toward Vaccination Against SARS-COV-2 in Pediatric Patients with Heart Disease Invited Reviewed

Yanagisawa, A. Torii, Y. Go, K. Kawada, J. I. Narita, A. Goto, A. Enomoto, S. Nishinosono, T. Yamaguchi, K. Kidokoro, H. Sato, Y. Takahashi, Y.

Pediatr Cardiol 2026.2

Association Between Adeno-associated Virus 2 and Neurologic Complications of Pediatric Human Herpesvirus-6B Infection

Jun-ichi Kawada, Yuki Higashimoto, Yoshiki Kawamura, Fumihiko Hattori, Mao Ite, Yuna Kawasaki, Hiroki Miura, Ken-ichi Iwata, Yuka Torii, Tetsushi Yoshikawa

Pediatric Infectious Disease Journal Vol. 44 ( 12 ) page： 1231 - 1236 2025.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

Background:

Recent studies have reported the possible link between adeno-associated virus 2 (AAV2) and severe pediatric acute hepatitis. It has been suggested that aberrant AAV2 replication initiated by coinfection with “helper viruses” such as human adenovirus and human herpesvirus-6B (HHV-6B) may induce abnormal immune responses. Encephalitis/encephalopathy is a severe complication of primary HHV-6B infection, but the underlying mechanisms remain unclear. This study analyzed the association between AAV2 coinfection and neurologic complications of primary HHV-6B infection in children.

Methods:

Preserved serum samples obtained from 36 patients with HHV-6B-associated encephalitis/encephalopathy, 39 with febrile seizure, and 83 without neurologic complications were retrospectively analyzed. Primary HHV-6B infection was confirmed if HHV-6B DNA was detected and the HHV-6B antibody was negative in serum. AAV2 and HHV-6 DNA loads were quantitated using real-time PCR.

Results:

AAV2 was detected in 4 (11%) and 3 (8%) patients in the encephalitis/encephalopathy and febrile seizure groups, respectively. In contrast, AAV2 was undetectable in 83 patients without neurologic complications. AAV2 detection frequency was significantly higher in the encephalitis/encephalopathy and febrile seizure groups compared with the no neurologic complications group (P = 0.01 and P = 0.03, respectively). Among 4 patients with HHV-6B-associated encephalitis/encephalopathy, AAV2 DNA was detected in the cerebrospinal fluid of 2 patients. Serum HHV-6B DNA load was not significantly different among patients who were AAV2 positive or AAV negative and with or without neurologic complications.

Conclusions:

These findings suggest that coinfection of AAV2 and HHV-6B is associated with neurologic complications such as encephalitis/encephalopathy and febrile seizure in children.

DOI： 10.1097/INF.0000000000004924

Associations of Nucleoside Diphosphate-Linked Moiety X-Type Motif 15 Variants With Neutropenia During Antiviral Therapy for Cytomegalovirus Disease in Pediatric Liver Transplant Recipients Reviewed Open Access

Iwata, K; Torii, Y; Fukuda, Y; Haruta, K; Yamaguchi, M; Suzuki, T; Ogura, Y; Kawada, J

TRANSPLANT INFECTIOUS DISEASE Vol. 27 ( 5 ) page： e70079 2025.9

Authorship：Corresponding author Language：English Publisher：Transplant Infectious Disease

Background: Cytomegalovirus (CMV) infection in pediatric liver transplant recipients is a major concern. Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line treatment agents; however, neutropenia is a common adverse effect. Nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are linked to thiopurine-induced myelosuppression; however, their associations with GCV/VGCV-induced cytotoxicity remain unclear. We aimed to examine the association between loss-of-function variants of the NUDT15 genotype and drug-related adverse reactions in pediatric transplant recipients, specifically liver transplant recipients, treated with GCV/VGCV. Methods: We retrospectively analyzed data from pediatric liver transplant recipients treated with GCV/VGCV for CMV disease or infection between 2012 and 2022. Patients were genotyped for NUDT15 R139C, R139H, and V18I variants, and hematological outcomes were compared between the normal and variant groups. Results: Of 40 patients, 10 (25%) harbored NUDT15 variants. The incidence rate of neutropenia (60% vs. 7%; p < 0.01) and percentage decrease in neutrophil count (−65.1% vs. −45.9%; p = 0.02) were significantly higher in the variant group than in the normal group. No significant differences were observed in the incidence of leukopenia, anemia, thrombocytopenia, hepatic toxicity, or renal toxicity. Conclusion: NUDT15 variants were associated with an increased risk of neutropenia in pediatric liver transplant recipients receiving GCV/VGCV treatment. Genetic screening before treatment initiation may help optimize antiviral therapy, minimize hematological toxicity, and improve patient management. Further studies are needed to refine the treatment strategies. (Figure presented.).

DOI： 10.1111/tid.70079

ヒトヘルペスウイルス6B初感染の中枢神経合併症とアデノ随伴ウイルス2の関連の検討

川田潤一, 東本祐紀, 河村吉紀, 服部文彦, 三浦浩樹, 岩田健一, 鳥居ゆか, 吉川哲史

臨床とウイルス Vol. 53 ( 3 ) page： 191 - 191 2025.9

Plasma Proteomic Profiles of Pediatric Patients With Human Herpesvirus 6B Encephalitis Following Umbilical Cord Blood Transplantation Open Access

Kazunori Haruta, Yuto Fukuda, Hisateru Yamaguchi, Yoshiki Kawamura, Takako Suzuki, Yuka Torii, Atsushi Narita, Hideki Muramatsu, Hiroyuki Kidokoro, Jun Natsume, Yoshiyuki Takahashi, Tetsushi Yoshikawa, Jun‐ichi Kawada

Journal of Medical Virology Vol. 97 ( 3 ) page： e70311 2025.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

ABSTRACT

Human herpesvirus 6B (HHV‐6B) encephalitis is a rare but severe complication of hematopoietic cell transplantation. This study investigated the pathogenesis of HHV‐6B encephalitis by comparing plasma proteomic profiles of four pediatric patients with HHV‐6B encephalitis to three with asymptomatic HHV‐6B reactivation following umbilical cord blood transplantation (UCBT). Plasma proteomic profiling was conducted using liquid chromatography‐mass spectrometry. Overall, 260 proteins were identified and quantified in plasma samples. At the onset of HHV‐6B encephalitis and asymptomatic reactivation, 20 and 24 proteins, respectively, were significantly upregulated compared to their respective pre‐onset levels. Of these, 11 proteins were uniquely upregulated in HHV‐6B encephalitis. S100‐A9 and S100‐A8 were the most and second‐most upregulated proteins in HHV‐6B encephalitis, respectively. Elevated plasma S100A8/A9 heterodimer levels were confirmed via enzyme‐linked immunosorbent assay in three of the four patients with HHV‐6B encephalitis. Pathway analysis identified neutrophil degranulation as the most enriched category among upregulated proteins in HHV‐6B encephalitis. Additionally, proteins related to the protein‐lipid complex remodeling pathway were more prominently upregulated in HHV‐6B encephalitis than in asymptomatic reactivation. Proteomic analysis revealed distinct plasma protein profiles between HHV‐6B encephalitis and asymptomatic HHV‐6B reactivation in pediatric UCBT recipients. The inflammatory response mediated by S100A8/A9 proteins may play a critical role in the pathogenesis of HHV‐6B encephalitis. These findings indicate that proteomic analysis may provide novel insights into the host response to HHV‐6B reactivation and the subsequent development of HHV‐6B encephalitis.

DOI： 10.1002/jmv.70311

Metagenomic Analysis of Lung Microbiome in Patients With Interstitial Lung Diseases and Sarcoidosis: An Experimental Study Open Access

Suguru Takeuchi, Jun‐ichi Kawada, Atsushi Suzuki, Koji Sakamoto, Yuto Fukuda, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Yuichiro Shindo, Yoshinori Ito

Health Science Reports Vol. 8 ( 2 ) page： e70328 2025.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

ABSTRACT

Background and Aims

Interactions between the lung microbiome and pulmonary epithelium plays a pivotal role in shaping immunity in the lung. Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD). Some patients with IPF develop episodic acute exacerbations often associated with microbial dysbiosis in the lungs. This study aimed to investigate etiologic agents as well as the lung microbiome in patients with ILDs and sarcoidosis.

Methods

This study analyzed 31 patients divided into the IPF (IPF‐stable, n = 12), acute exacerbation of ILDs (AE‐ILDs, n = 6), and sarcoidosis (n = 13) groups. Bronchoalveolar lavage fluid (BALF) samples were analyzed by RNA‐based metagenomic next‐generation sequencing (NGS) on an Illumina platform.

Results

In total, 87 pathogens were detected using metagenomic NGS at the genus level. Prevotella, Streptococcus, and Veillonella dominated the BALF microbial communities, and sequence reads of these bacteria were abundant, especially in the sarcoidosis group. Conversely, only a small number of bacterial reads were detected in the AE‐ILDs group, and the overall proportion of microbial composition differed from that of the other groups. No significant difference was found in community diversity (α‐diversity) among the groups, whereas the structural similarity of the microflora (β‐diversity) differed significantly between the AE‐ILDs and sarcoidosis groups.

Conclusions

Bacterial sequence reads in BALF were smaller in both the IPF‐stable and AE‐ILD groups than in the sarcoidosis group. Dysbiosis in the lung microbiome has been observed in patients with AE‐ILD and may be related to the progression of inflammation.

DOI： 10.1002/hsr2.70328

Association between adeno-associated virus 2 and severe acute hepatitis of unknown etiology in Japanese children.

Iwata KI, Torii Y, Sakai A, Fukuda Y, Haruta K, Yamaguchi M, Suzuki T, Etani Y, Takahashi Y, Umetsu S, Inui A, Sumazaki R, Kawada JI

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 31 ( 1 ) page： 102462 2025.1

The landscape of 142 Epstein-Barr viral whole genomes in gastric cancer

Kojima, Y; Hamada, M; Naruse, A; Goto, K; Khine, HT; Arai, H; Akutsu, Y; Satou, A; Nakaguro, M; Kato, S; Kodera, Y; Yatabe, Y; Torii, Y; Kawada, JI; Murata, T; Kimura, H; Takiguchi, S; Inagaki, H; Kataoka, H; Okuno, Y

JOURNAL OF GASTROENTEROLOGY Vol. 60 ( 1 ) page： 55 - 65 2025.1

Successful treatment of rapidly progressive Epstein-Barr virus-associated lymphoproliferative disorder with upfront allogeneic hematopoietic cell transplantation

YAE Hidekatsu, NISHIMOTO Mitsutaka, KAWAZOE Mai, TORII Yuka, KAWADA Jun-ichi, KUNO Masatomo, OKAMURA Hiroshi, NAKASHIMA Yasuhiro, NAKAMAE Mika, HINO Masayuki, NAKAMAE Hirohisa

Rinsho Ketsueki Vol. 66 ( 10 ) page： 1293 - 1297 2025

Authorship：Lead author Language：Japanese Publisher：The Japanese Society of Hematology

<p>A 54-year-old woman presented with a chief concern of right back pain that had persisted for 3 weeks. Laboratory tests revealed pancytopenia, liver dysfunction, and coagulation abnormalities. She had hepatomegaly and splenomegaly but no lymphadenopathy. No abnormal cells were detected in the bone marrow or on a liver biopsy. Epstein-Barr virus (EBV) DNA levels in the peripheral blood were high at 6.44 log IU/m<i>l</i>, and clonality of EBV-infected cells was confirmed by Southern blot hybridization with a probe targeting the EBV terminal repeat. EBV-infected NK cells were detected using the magnetic bead method. This led to a diagnosis of EBV-associated lymphoproliferative disease (EBV-LPD). As pancytopenia and coagulation abnormalities induced by the development of hemophagocytic syndrome continued to worsen after steroid therapy, we performed intensive chemotherapy followed by umbilical cord blood transplantation. After transplantation, EBV-DNA levels in the peripheral blood were undetectable, with complete donor chimerism. In the present case, the rapid disease progression with an extremely high EBV-DNA level indicated a poor prognosis. Intensive chemotherapy followed by upfront allogeneic hematopoietic cell transplantation may be necessary in patients with rapidly progressing EBV-LPD.</p>

DOI： 10.11406/rinketsu.66.1293

次世代シークエンサーを用いた血球貪食性リンパ組織球症の病原体診断

福田悠人, 堀場千尋, 岩田健一, 山口慎, 鈴木高子, 河邉慎司, 鳥居ゆか, 川田潤一

臨床とウイルス Vol. 52 ( 3 ) page： 130 - 130 2024.10

Serum proteomic profiles of patients with chronic recurrent multifocal osteomyelitis

Kawada, J; Yamaguchi, M; Haruta, K; Fukuda, Y; Iwata, K; Suzuki, T; Torii, Y

RHEUMATOLOGY 2024.6

Nanopore sequencing in distinguishing between wild-type and vaccine strains of Varicella-Zoster virus

Fukuda, Y; Suzuki, T; Iwata, KI; Haruta, K; Yamaguchi, M; Torii, Y; Narita, A; Muramatsu, H; Takahashi, Y; Kawada, JI

VACCINE Vol. 42 ( 11 ) page： 2927 - 2932 2024.4

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis

Suzuki, T; Sato, Y; Okuno, Y; Torii, Y; Fukuda, Y; Haruta, K; Yamaguchi, M; Kawamura, Y; Hama, A; Narita, A; Muramatsu, H; Yoshikawa, T; Takahashi, Y; Kimura, H; Ito, Y; Kawada, JI

JOURNAL OF CLINICAL IMMUNOLOGY Vol. 44 ( 4 ) page： 103 2024.4

MicroRNA expression profiling of urine exosomes in children with congenital cytomegalovirus infection

Torii, Y; Suzuki, T; Fukuda, Y; Haruta, K; Yamaguchi, M; Horiba, K; Kawada, JI; Ito, Y

SCIENTIFIC REPORTS Vol. 14 ( 1 ) page： 5475 2024.3

Comparison of Whole Blood and Plasma for Monitoring Cytomegalovirus and Epstein-Barr Virus

Fukuda, Y; Torii, Y; Iwata, K; Haruta, K; Yamaguchi, M; Suzuki, T; Narita, A; Muramatsu, H; Ogura, Y; Takahashi, Y; Ito, Y; Kawada, J

NEW MICROBIOLOGICA Vol. 47 ( 1 ) 2024.3

Comparison of plasma proteomic profiles of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and infectious mononucleosis

Haruta, K; Suzuki, T; Yamaguchi, M; Fukuda, Y; Torii, Y; Takahashi, Y; Ito, Y; Kawada, J

JOURNAL OF MEDICAL VIROLOGY Vol. 96 ( 2 ) page： e29450 2024.2

Next-generation sequencing-based detection of <i>Ureaplasma</i> in the gastric fluid of neonates with respiratory distress and chorioamnionitis Open Access

Okumura, T; Horiba, K; Tetsuka, N; Sato, Y; Sugiyama, Y; Haruta, K; Yamaguchi, M; Suzuki, T; Torii, Y; Kawada, J; Ogi, T; Hayakawa, M; Ito, Y

JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE Vol. 36 ( 1 ) page： 2207113 2023.12

特集エキスパートが教える小児の薬物治療 Ⅲ.疾患別 B.感染症サイトメガロウイルス感染症

鳥居ゆか, 川田潤一

小児内科 Vol. 55 ( 13 ) page： 300 - 304 2023.11

Proteomic Analysis Reveals Novel Plasma Biomarkers for Neurological Complications in Patients With Congenital Cytomegalovirus Infection

Yamaguchi, M; Suzuki, T; Kidokoro, H; Iwata, K; Fukuda, Y; Haruta, K; Torii, Y; Ito, Y; Kawada, J

JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY Vol. 12 ( 10 ) page： 525 - 533 2023.10

特集古くて新しい予防接種～この10年で何が変わったか～ Ⅰ.総論接種に注意を要する場合と対応

鳥居ゆか, 伊藤嘉規

小児科診療 Vol. 86 ( 10 ) page： 1171 - 1176 2023.10

Association Between <i>NUDT15 R139C</i> Genotype and Neutropenia During Antiviral Therapy in Patients With Congenital Cytomegalovirus Infection

Yamaguchi, M; Iwata, KI; Fukuda, Y; Haruta, K; Suzuki, T; Torii, Y; Ito, Y; Kawada, JI

PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 42 ( 7 ) page： E256 - E257 2023.7

Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation Open Access

Haruta, K; Takeuchi, S; Yamaguchi, M; Horiba, K; Suzuki, T; Torii, Y; Narita, A; Muramatsu, H; Takahashi, Y; Ito, Y; Kawada, JI

JOURNAL OF MOLECULAR DIAGNOSTICS Vol. 25 ( 6 ) page： 403 - 409 2023.6

Utility of nanopore sequencing for detecting pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure Open Access

Yamaguchi, M; Horiba, K; Haruta, K; Takeuchi, S; Suzuki, T; Torii, Y; Kawabe, S; Wada, S; Ikeyama, T; Ito, Y; Ogi, T; Kawada, JI

JOURNAL OF CLINICAL VIROLOGY PLUS Vol. 3 ( 2 ) 2023.6

トピックス 2017～2021年に当院で後天性サイトメガロウイルス感染症と診断された超早産児の検討

白川雄一, 杉山裕一朗, 鈴木道雄, 鳥居ゆか, 伊藤嘉規, 久保田哲夫, 服部哲夫, 加藤有一

小児科 Vol. 64 ( 5 ) page： 525 - 530 2023.5

Correlation of cytomegalovirus viral load between whole blood and plasma of congenital cytomegalovirus infection under valganciclovir treatment Open Access

Torii, Y; Morioka, I; Kakei, Y; Fujioka, K; Kakimoto, Y; Takahashi, N; Yoshikawa, T; Moriuchi, H; Oka, A; Ito, Y

BMC INFECTIOUS DISEASES Vol. 23 ( 1 ) page： 31 2023.1

Time course of skin rash, computed tomography findings, and viral load in a rheumatoid arthritis patient with severe varicella pneumonia Open Access

Kobayashi, H; Takeuchi, S; Torii, Y; Ikenouchi, T; Kawada, J; Oka, K; Kato, S; Ogawa, M

IDCASES Vol. 33 page： e01866 2023

Post-exposure prophylaxis to prevent varicella in immunocompromised children Open Access

Yamaguchi, M; Tetsuka, N; Okumura, T; Haruta, K; Suzuki, T; Torii, Y; Kawada, JI; Ito, Y

INFECTION PREVENTION IN PRACTICE Vol. 4 ( 4 ) page： 100242 2022.12

Performance of Nanopore and Illumina Metagenomic Sequencing for Pathogen Detection and Transcriptome Analysis in Infantile Central Nervous System Infections Open Access

Horiba, K; Torii, Y; Aizawa, Y; Yamaguchi, M; Haruta, K; Okumura, T; Suzuki, T; Kawano, Y; Kawada, JI; Hara, S; Saitoh, A; Giske, CG; Ogi, T; Ito, Y

OPEN FORUM INFECTIOUS DISEASES Vol. 9 ( 10 ) page： ofac504 2022.10

Quantitative assessment of viral load in the blood and urine of patients with congenital cytomegalovirus infection using droplet digital PCR Open Access

Yamaguchi, M; Kawada, J; Torii, Y; Haruta, K; Suzuki, T; Horiba, K; Takahashi, Y; Ito, Y

JOURNAL OF MEDICAL VIROLOGY Vol. 94 ( 9 ) page： 4559 - 4564 2022.9

Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study Open Access

Torii, Y; Horiba, K; Kawada, J; Haruta, K; Yamaguchi, M; Suzuki, T; Uryu, H; Kashiwa, N; Goishi, K; Ogi, T; Ito, Y

BMC INFECTIOUS DISEASES Vol. 22 ( 1 ) page： 568 2022.6

MicroRNA expression profiling of cerebrospinal fluid/serum exosomes in children with human herpesvirus 6-associated encephalitis/encephalopathy by high-throughput sequencing

Torii, Y; Kawada, J; Horiba, K; Okumura, T; Suzuki, T; Ito, Y

JOURNAL OF NEUROVIROLOGY Vol. 28 ( 1 ) page： 151 - 157 2022.2

Next-Generation Sequencing to Detect Pathogens in Pediatric Febrile Neutropenia: A Single-Center Retrospective Study of 112 Cases Open Access

Kazuhiro Horiba, Yuka Torii, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Hideki Muramatsu, Yoshiyuki Takahashi, Tomoo Ogi, Yoshinori Ito

Open Forum Infectious Diseases Vol. 8 ( 11 ) page： ofab223 2021.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

<title>Abstract</title>
<sec>
<title>Background</title>
Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to idenjpgy the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN.

</sec>
<sec>
<title>Methods</title>
FN is defined as 1) a neutrophil count &lt; 500/µL, and 2) fever ≥ 37.5 °C. Plasma/serum samples of 112 pediatric patients with FN, 10 patients with neutropenia without fever (NE), were sequenced by NGS and analyzed by a metagenomic pipeline PATHDET.

</sec>
<sec>
<title>Results</title>
The putative pathogens were detected by NGS in 5 of 10 patients with FN with positive for blood culture results, 15 of 87 patients (17%) with negative for blood culture results, and 3 of 8 patients with NE. Several bacteria that were common in the oral, skin, and gut flora were commonly detected in blood samples, suggesting translocation of the human microbiota to the bloodstream in the setting of neutropenia. The cluster analysis of the microbiota in blood samples using NGS demonstrated that the representative bacteria of each cluster was mostly consistent with the pathogens in each patient.

</sec>
<sec>
<title>Conclusions</title>
NGS technique has a great potential for detecting causative pathogens in patients with FN. Cluster analysis, which extracts characteristic microorganisms from a complex microbial population, may be effective to detect pathogens in minute quantities of microbiota, such as those from the bloodstream.

</sec>

DOI： 10.1093/ofid/ofab223

A Case of Descending Necrotizing Mediastinitis in a Previously Healthy Child Open Access

Okumura, T; Tetsuka, N; Yamaguchi, M; Suzuki, T; Torii, Y; Kawada, J; Ito, Y

CASE REPORTS IN PEDIATRICS Vol. 2021 page： 3159092 2021.9

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

Kazuhiro Horiba, Michio Suzuki, Nobuyuki Tetsuka, Yoshihiko Kawano, Makoto Yamaguchi, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Jun-Ichi Kawada, Makoto Morita, Shinya Hara, Tomoo Ogi, Yoshinori Ito

BMC infectious diseases Vol. 21 ( 1 ) page： 531 - 531 2021.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1186/s12879-021-06231-3

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

Hiroyuki Kidokoro, Anna Shiraki, Yuka Torii, Masaharu Tanaka, Hiroyuki Yamamoto, Hirokazu Kurahashi, Koichi Maruyama, Akihisa Okumura, Jun Natsume, Yoshinori Ito

Neuroradiology Vol. 63 ( 5 ) page： 761 - 768 2021.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1007/s00234-020-02603-9

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

Okumura, T; Horiba, K; Kamei, H; Takeuchi, S; Suzuki, T; Torii, Y; Kawada, J; Takahashi, Y; Ogura, Y; Ogi, T; Ito, Y

BMC MICROBIOLOGY Vol. 21 ( 1 ) page： 104 2021.4

Authorship：Lead author Language：English Publisher：BMC Microbiology

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.

DOI： 10.1186/s12866-021-02154-w

Immune cell infiltration landscapes in pediatric acute myocarditis analyzed by CIBERSORT Open Access

Kawada, J; Takeuchi, S; Imai, H; Okumura, T; Horiba, K; Suzuki, T; Torii, Y; Yasuda, K; Imanaka-Yoshida, K; Ito, Y

JOURNAL OF CARDIOLOGY Vol. 77 ( 2 ) page： 174 - 178 2021.2

Authorship：Lead author Language：English Publisher：Journal of Cardiology

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.

DOI： 10.1016/j.jjcc.2020.08.004

Viral Reactivations in Children with Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Narita, A; Ito, Y; Kawashima, N; Okuno, Y; Muramatsu, H; Nishio, N; Torii, Y; Kawada, J; Kojima, S; Takahashi, Y

PEDIATRIC BLOOD & CANCER Vol. 67 2020.12

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

Suguru Takeuchi, Jun-Ichi Kawada, Kazuhiro Horiba, Makoto Yamaguchi, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Shinji Kawabe, Sho Wada, Takanari Ikeyama, Yoshinori Ito

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Vol. 21 ( 11 ) page： E1026 - E1030 2020.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1097/PCC.0000000000002558

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

Yuka Torii, Kazuhiro Horiba, Satoshi Hayano, Taichi Kato, Takako Suzuki, Jun-Ichi Kawada, Yoshiyuki Takahashi, Seiji Kojima, Yusuke Okuno, Tomoo Ogi, Yoshinori Ito

BMC pediatrics Vol. 20 ( 1 ) page： 482 - 482 2020.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1186/s12887-020-02380-7

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

Takako Suzuki, Jun-Ichi Kawada, Eri Nishikawa, Yuka Torii, Kazuhiro Horiba, Suguru Takeuchi, Toshihiko Okumura, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshinori Ito

Bone marrow transplantation Vol. 55 ( 9 ) page： 1872 - 1874 2020.9

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

Jun-Ichi Kawada, Yasuko Kamiya, Akihisa Sawada, Keiji Iwatsuki, Koji Izutsu, Yuka Torii, Hiroshi Kimura, Yoshinori Ito

The Journal of infectious diseases Vol. 220 ( 8 ) page： 1307 - 1311 2019.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1093/infdis/jiz315

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

Suguru Takeuchi, Jun-Ichi Kawada, Kazuhiro Horiba, Yusuke Okuno, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Shinji Kawabe, Sho Wada, Takanari Ikeyama, Yoshinori Ito

Scientific reports Vol. 9 ( 1 ) page： 12909 - 12909 2019.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1038/s41598-019-49372-x

Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection. International journal Open Access

Yuka Torii, Shigeru Yoshida, Yoichiro Yanase, Takashi Mitsui, Kazuhiro Horiba, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-Ichi Kawada, Tomomi Kotani, Mamoru Yamashita, Yoshinori Ito

BMC pregnancy and childbirth Vol. 19 ( 1 ) page： 205 - 205 2019.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1186/s12884-019-2360-1

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

Suguru Takeuchi, Jun-Ichi Kawada, Yusuke Okuno, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Kazushi Yasuda, Atsushi Numaguchi, Taichi Kato, Yoshiyuki Takahashi, Yoshinori Ito

Journal of medical virology Vol. 90 ( 12 ) page： 1814 - 1821 2018.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/jmv.25263

Risk Factors for Viral Infections in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Narita, A; Ito, Y; Torii, Y; Kawada, JI; Miwata, S; Narita, K; Kitazawa, H; Hamada, M; Kataoka, S; Ichikawa, D; Ito, R; Murakami, N; Kojima, D; Suzuki, K; Nishikawa, E; Kawashima, N; Okuno, Y; Muramatsu, H; Hama, A; Kojima, S; Takahashi, Y

BONE MARROW TRANSPLANTATION Vol. 53 page： 588 - 589 2018.9

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

Lee-Yoshimoto Minsoo, Goishi Keiji, Torii Yuka, Ito Yoshinori, Ono Hiroya, Mori Tomoko, Kashiwa Naoyuki, Hosokawa Shinichi, Shichino Hiroyuki

Japanese Journal of Infectious Diseases Vol. 71 ( 4 ) page： 309 - 311 2018.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：National Institute of Infectious Diseases, Japanese Journal of Infectious Diseases Editorial Committee

<p>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.</p>

DOI： 10.7883/yoken.jjid.2017.577

Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells. International journal Open Access

Jun-Ichi Kawada, Shotaro Ando, Yuka Torii, Takahiro Watanabe, Yoshitaka Sato, Yoshinori Ito, Hiroshi Kimura

Cancer medicine Vol. 7 ( 4 ) page： 1275 - 1284 2018.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/cam4.1311

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

Kazuhiro Horiba, Jun-Ichi Kawada, Yusuke Okuno, Nobuyuki Tetsuka, Takako Suzuki, Shotaro Ando, Yasuko Kamiya, Yuka Torii, Tetsuya Yagi, Yoshiyuki Takahashi, Yoshinori Ito

Scientific reports Vol. 8 ( 1 ) page： 3784 - 3784 2018.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1038/s41598-018-22133-y

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

Takako Suzuki, Jun-Ichi Kawada, Yusuke Okuno, Satoshi Hayano, Kazuhiro Horiba, Yuka Torii, Yoshiyuki Takahashi, Syuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Yoshinori Ito

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology Vol. 96 page： 67 - 72 2017.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jcv.2017.10.001

Metabolome analysis reveals the association between the kynurenine pathway and human herpesvirus 6 encephalopathy in immunocompetent children

Yuka Torii, Yoshihiko Kawano, Hajime Sato, Tamaki Fujimori, Kazunori Sasaki, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

METABOLOMICS Vol. 13 ( 11 ) 2017.11

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Introduction Human herpesvirus 6 (HHV-6) is the second most common causative pathogen of acute encephalopathy in immunocompetent children in Japan. Identification of biomarkers associated the pathophysiology is desirable to monitor disease severity, progression, and prognosis.Objectives To investigate potential biomarkers for HHV-6 encephalopathy, serum metabolome profiling was analyzed and candidate metabolites were investigated the function in the diseases.Methods Pediatric patients with HHV-6 encephalopathy (n = 8), febrile seizure (n = 20), and febrile infection without febrile seizure (n = 7) were enrolled in this study, and serum metabolites were identified and quantified. For further analysis, serum samples of HHV-6 infected patients were analyzed by absolute quantification assay for kynurenine (KYN) and quinolinic acid (QUIN) in a total of 38 patients with or without encephalopathy. An in vitro blood-brain barrier (BBB) model was used to evaluate the effect of KYN and QUIN on BBB integrity because BBB damage induces brain edema.Results Metabolome profiling identified 159 metabolites in serum samples. The levels of KYN and QUIN, which belong to the tryptophan-KYN pathway, were significantly higher in the HHV-6 encephalopathy group than the other two groups. When quantified in the larger patient group, remarkably high levels of KYN and QUIN were observed exclusively in the encephalopathy group. Trans-endothelial electrical resistance of the BBB model was significantly decreased after QUIN treatment in culture.Conclusion Metabolome analysis revealed that KYN and QUIN may be associated with the pathophysiology of HHV-6 encephalopathy. In particular, QUIN may damage BBB integrity.

DOI： 10.1007/s11306-017-1268-x

Epstein-Barr virus infection-induced inflammasome activation in human monocytes. International journal Open Access

Yuka Torii, Jun-Ichi Kawada, Takayuki Murata, Hironori Yoshiyama, Hiroshi Kimura, Yoshinori Ito

PloS one Vol. 12 ( 4 ) page： e0175053 2017.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1371/journal.pone.0175053

Analysis of circulating human and viral microRNAs in patients with congenital cytomegalovirus infection Open Access

Kawano, Y; Kawada, J; Kamiya, Y; Suzuki, M; Torii, Y; Kimura, H; Ito, Y

JOURNAL OF PERINATOLOGY Vol. 36 ( 12 ) page： 1101 - 1105 2016.12

Authorship：Lead author Language：English Publisher：Journal of Perinatology

Objective:Cytomegalovirus (CMV) is the most common cause of congenital infection and can cause neurodevelopmental disabilities, although a majority of patients are asymptomatic. Biomarkers associated with disease severity would be desirable to distinguish asymptomatic from mildly symptomatic patients who may benefit from antiviral treatment. MicroRNAs (miRNAs) are noncoding RNAs that may have the potential to serve as biomarkers.Study Design:Thirteen infants with congenital CMV infection were enrolled, and plasma levels of 11 human- and 3 CMV-encoded miRNAs were quantitated by real-time PCR. Plasma levels of miRNAs and their associations with clinical features were evaluated.Results:The levels of miR-183-5p and miR-210-3p were significantly higher in patients with congenital CMV infection than in control infants, whereas no significant associations between levels of miRNAs and clinical features of congenital CMV infection were observed.Conclusion:Plasma miRNAs could be associated with the pathogenesis of congenital CMV infection and could be used as disease biomarkers.

DOI： 10.1038/jp.2016.157

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

Yasuko Kamiya, Tadao Hasegawa, Yasuhiko Takegami, Kazuhiro Horiba, Shotaro Ando, Yuka Torii, Hiroyuki Kidokoro, Taichi Kato, Jun Natsume, Jun-Ich Kawada, Yoshinori Ito

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 22 ( 12 ) page： 811 - 814 2016.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jiac.2016.06.011

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

Shotaro Ando, Jun-Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura

Oncotarget Vol. 7 ( 47 ) page： 76793 - 76805 2016.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.18632/oncotarget.12529

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

Jun-Ichi Kawada, Yusuke Okuno, Yuka Torii, Ryo Okada, Satoshi Hayano, Shotaro Ando, Yasuko Kamiya, Seiji Kojima, Yoshinori Ito

Scientific reports Vol. 6 page： 33452 - 33452 2016.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1038/srep33452

Quantitative metabolome profiling reveals the involvement of the kynurenine pathway in influenza-associated encephalopathy

Yuka Torii, Yoshihiko Kawano, Hajime Sato, Kazunori Sasaki, Tamaki Fujimori, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

METABOLOMICS Vol. 12 ( 5 ) 2016.5

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Introduction Influenza-associated encephalopathy is a serious complication of influenza and is the most common form of acute encephalitis/encephalopathy in Japan. The number of reports from other countries is increasing, reflecting international recognition and concern.Objectives Identification of a specific biomarker could provide important clues about the pathophysiology of influenza-associated encephalopathy.Methods During the 2009-2011 flu seasons, 34 pediatric patients hospitalized with influenza complications, including influenza-associated encephalopathy, were enrolled in the study. Serum samples were collected during the acute and convalescent phases of disease. Patients were classified into encephalopathy (n = 12) and non-encephalopathy (n = 22) groups. Serum metabolites were identified and quantified by capillary electrophoresis coupled with time-of-flight mass spectrometry. Quantified data were evaluated for comparative analysis. Subsequently, a total of 55 patients with or without encephalopathy were enrolled for absolute quantification of serum kynurenine and quinolinic acid.Results Based on m/z values and migration times, 136 metabolites were identified in serum samples. During the acute phase of disease, three metabolites (succinic acid, undecanoic acid, and kynurenine) were significantly higher, and two other metabolites (decanoic acid and cystine) were significantly lower, in the encephalopathy group compared to the non-encephalopathy group (p = 0.012, 0.022, 0.044, 0.038, 0.046, respectively). In a larger patient group, serum kynurenine and its downstream product in tryptophan metabolism, quinolinic acid, a known neurotoxin, were significantly higher in the encephalopathy than the non-encephalopathy without febrile seizure group.Conclusion Comprehensive metabolite profiles revealed five metabolites as potential biomarkers for influenza-associated encephalopathy; the tryptophan-kynurenine metabolic process could be associated with its pathophysiology.

DOI： 10.1007/s11306-016-1011-z

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

Shaimaa Elmahdi, Hideki Muramatsu, Atsushi Narita, Yuka Torii, Olfat Ismael, Nozomu Kawashima, Yusuke Okuno, Yuko Sekiya, Yinyan Xu, Xinan Wang, Asahito Hama, Yoshinori Ito, Yoshiyuki Takahashi, Seiji Kojima

Pediatric transplantation Vol. 20 ( 1 ) page： 105 - 113 2016.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/petr.12620

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

Nozomu Kawashima, Hideki Muramatsu, Yusuke Okuno, Yuka Torii, Jun-ichi Kawada, Atsushi Narita, Koji Nakanishi, Asahito Hama, Aya Kitamura, Naoya Asai, Shigeo Nakamura, Yoshiyuki Takahashi, Yoshinori Ito, Seiji Kojima

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 21 ( 12 ) page： 857 - 863 2015.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jiac.2015.08.018

Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis. International journal

Yasuko Kamiya, Jun-ichi Kawada, Yoshihiko Kawano, Yuka Torii, Shinji Kawabe, Naomi Iwata, Yoshinori Ito

Clinical rheumatology Vol. 34 ( 10 ) page： 1705 - 1712 2015.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1007/s10067-015-2922-1

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

Jun-ichi Kawada, Yuka Torii, Yoshihiko Kawano, Michio Suzuki, Yasuko Kamiya, Tomomi Kotani, Fumitaka Kikkawa, Hiroshi Kimura, Yoshinori Ito

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology Vol. 65 page： 41 - 45 2015.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jcv.2015.01.015

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

Michio Suzuki, Yuka Torii, Jun-ichi Kawada, Hiroshi Kimura, Hideya Kamei, Yasuharu Onishi, Kenitiro Kaneko, Hisami Ando, Tetsuya Kiuchi, Yoshinori Ito

Microbiology and immunology Vol. 57 ( 10 ) page： 715 - 722 2013.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/1348-0421.12086

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

Yoshinori Ito, Hiroshi Kimura, Yuka Torii, Masahiro Hayakawa, Toshihiro Tanaka, Hitoshi Tajiri, Yuko Yoto, Keiko Tanaka-Taya, Hirokazu Kanegane, Akiyoshi Nariai, Hiroshi Sakata, Hiroyuki Tsutsumi, Megumi Oda, Shumpei Yokota, Tsuneo Morishima, Hiroyuki Moriuchi

Pediatrics international : official journal of the Japan Pediatric Society Vol. 55 ( 5 ) page： 566 - 571 2013.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/ped.12122

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

Yoshihiko Kawano, Seiko Iwata, Jun-ichi Kawada, Kensei Gotoh, Michio Suzuki, Yuka Torii, Seiji Kojima, Hiroshi Kimura, Yoshinori Ito

The Journal of infectious diseases Vol. 208 ( 5 ) page： 771 - 779 2013.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1093/infdis/jit222

Clinicoepidemiologic status of mother-to-child infections: a nationwide survey in Japan. International journal Open Access

Yuka Torii, Hiroshi Kimura, Yoshinori Ito, Masahiro Hayakawa, Toshihiro Tanaka, Hitoshi Tajiri, Yuko Yoto, Keiko Tanaka-Taya, Hirokazu Kanegane, Akiyoshi Nariai, Hiroshi Sakata, Hiroyuki Tsutsumi, Megumi Oda, Shumpei Yokota, Tsuneo Morishima, Hiroyuki Moriuchi

The Pediatric infectious disease journal Vol. 32 ( 6 ) page： 699 - 701 2013.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1097/INF.0b013e3182897c36

Remission of juvenile idiopathic arthritis with primary Epstein-Barr virus infection. International journal Open Access

Jun-Ichi Kawada, Yoshinori Ito, Yuka Torii, Hiroshi Kimura, Naomi Iwata

Rheumatology (Oxford, England) Vol. 52 ( 5 ) page： 956 - 958 2013.5

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

Yuka Torii, Hiroshi Kimura, Kazuhiko Hayashi, Michio Suzuki, Jun-Ichi Kawada, Seiji Kojima, Yoshiaki Katano, Hidemi Goto, Yoshinori Ito

Microbiology and immunology Vol. 57 ( 2 ) page： 118 - 121 2013.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/1348-0421.12009

Increased levels of cytokines and high-mobility group box 1 are associated with the development of severe pneumonia, but not acute encephalopathy, in 2009 H1N1 influenza-infected children. International journal

Yoshinori Ito, Yuka Torii, Rieko Ohta, Masaki Imai, Shinya Hara, Yoshihiko Kawano, Tadashi Matsubayashi, Ayano Inui, Tetsushi Yoshikawa, Naoko Nishimura, Takao Ozaki, Tsuneo Morishima, Hiroshi Kimura

Cytokine Vol. 56 ( 2 ) page： 180 - 187 2011.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The 2009 A(H1N1) influenza virus has caused a large outbreak, and resulted in major complications of severe pneumonia and acute encephalopathy in the pediatric population in Japan. METHODS: This study examined six patients with acute encephalopathy, 34 patients with severe pneumonia, five patients with both pneumonia and encephalopathy, and 46 patients without severe complications. The concentrations of 27 cytokines were examined in the cerebrospinal fluid of patients with encephalopathy, and the levels of these cytokines, Cytochrome c, high-mobility group box 1 (HMGB1) were measured in the serum of all patients. RESULTS: Patients with severe pneumonia had higher serum concentrations of 16 cytokines, including Th1 cytokines, Th2 cytokines, chemokines, and growth factors, than patients with uncomplicated influenza. The distribution of 27 cytokines in the CSF did not parallel the serum levels in 11 patients with acute encephalopathy. HMGB1 concentrations in the serum were significantly higher in pneumonia patients with or without encephalopathy than in uncomplicated influenza patients, and were significantly associated with the upregulation of 10 cytokines. CONCLUSIONS: Elevated levels of Th2 cytokines appear to be unique to influenza caused by 2009 H1N1 influenza virus and HMGB1 could play an important role in the pathogenesis of severe pneumonia. There appear to be different pathologic processes for encephalopathy and pneumonia.

DOI： 10.1016/j.cyto.2011.07.016

Immunogenicity of inactivated 2009 H1N1 influenza vaccine in pediatric liver transplant recipients. International journal

Yuka Torii, Hiroshi Kimura, Nobuhiko Ochi, Kenitiro Kaneko, Hisami Ando, Tetsuya Kiuchi, Yoshinori Ito

Vaccine Vol. 29 ( 25 ) page： 4187 - 4189 2011.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

To assess the safety and immunogenicity of 2009 H1N1 influenza vaccination, 13 pediatric liver transplant recipients and 31 immunocompetent controls received inactivated influenza vaccine without adjuvant according to Japanese guidelines. Serious adverse events and acute allograft rejections were not observed in participants. Seroprotection rates (hemagglutinin-inhibition (HI) antibody titer ≥ 1:40) were 53.8% among recipients and 58.1% among controls (p=0.797). Seroconversion rates (4-fold or more HI antibody rise) were 46.2% for the recipient group and 51.6% for the control group (p=0.741). Geometric mean titers were elevated after vaccination in both groups. In comparison with the seasonal influenza vaccination, the seroconversion rate for 2009 H1N1 appeared to be higher than that for seasonal influenza antigens, and the seroprotection rate for 2009 H1N1 clearly increased after vaccination. These findings suggest that pediatric liver transplant patients may respond safely to inactivated 2009 H1N1 influenza vaccines in a manner similar to immunocompetent children.

DOI： 10.1016/j.vaccine.2011.04.012

Serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with 2009 H1N1 influenza. International journal Open Access

Rieko Ohta, Yuka Torii, Masaki Imai, Hiroshi Kimura, Noriko Okada, Yoshinori Ito

Microbiology and immunology Vol. 55 ( 3 ) page： 191 - 198 2011.3

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal)

Anaphylatoxins (C5a, C4a, and C3a) are fragments of activated complement and are leading mediators of the inflammatory response for controlling viral infection. However, an excessive response may increase the severity of infectious diseases. Serum concentrations of proinflammatory mediators, including cytokines, high-mobility group box 1 and anaphylatoxins, were measured in pediatric 2009 H1N1 influenza patients in order to investigate the pathology of this new influenza. The concentrations of all three anaphylatoxins were significantly enhanced by 2009 H1N1 influenza infection. However, there were no significant differences in anaphylatoxin concentrations between 2009 H1N1 influenza patients with and without severe complications during the early stages of the disease. C3a concentrations dropped significantly during the recovery phase, whereas there were no significant differences between the acute and recovery phases in C5a and C4a concentrations. There was a correlation between C5a and IL-2. C4a was associated with IL-1ra, eotaxin, MCP-1, PDGFbb, and VEGF. C3a was correlated with IL-2 and IFN-γ. Taken together, these findings indicate that complement activation occurs in patients infected with 2009 H1N1 influenza virus and demonstrate that anaphylatoxins are involved in increased production of proinflammatory mediators in this new influenza.

DOI： 10.1111/j.1348-0421.2011.00309.x

Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome.

Yuka Torii, Hiroshi Yagasaki, Hidenori Tanaka, Seiji Mizuno, Nobuhiro Nishio, Hideki Muramatsu, Asahito Hama, Yoshiyuki Takahashi, Seiji Kojima

International journal of hematology Vol. 90 ( 2 ) page： 174 - 176 2009.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Kabuki syndrome (KS) is often associated with autoimmune abnormalities, such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, leukoplakia and thyroiditis, as well as congenital anomalies. We herein present a KS patient with refractory ITP who achieved durable and complete remission in response to a total of four once-monthly infusions of rituximab. KS patients are often more susceptible to infection, so splenectomy should be avoided. Therefore, rituximab therapy is an alternative option for KS patients with ITP who fail to respond to first-line therapy.

DOI： 10.1007/s12185-009-0387-1

Male gender is related to the development of parenteral nutrition-associated cholestasis in neonates Reviewed

Koji Takemoto, Atsushi Nakayama, Masatoki Ito, Yoshiaki Sato, Akiko Saito, Yuka Torii, Ken-Ichiro Kaneko, Hisami Ando, Masahiro Hayakawa

Journal of Neonatal-Perinatal Medicine Vol. 2 ( 4 ) page： 247 - 251 2009

　 PREV - NEXT 　

1