Publications by authors named "Akihiko Saitoh"

128 Publications

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan.

Pediatr Int 2021 Jul 7. Epub 2021 Jul 7.

The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan.

Background: Coronavirus disease 2019 (COVID-19) pandemic has affected the lives of young and old people. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than adults do. This is the first nationwide study that focused on pediatric cases reported by pediatricians, including those with no or mild symptoms, in Japan.

Methods: We analyzed the epidemiological and clinical characteristics, and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database that was voluntarily registered by the members of the Japan Pediatric Society.

Results: Almost half of patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively).

Conclusions: COVID-19 symptoms in pediatric cases are less severe than those in adult cases. School closure appeared to be limitedly effective, and controlling household transmission from adult family members is the most important measure for COVID-19 prevention among children.
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http://dx.doi.org/10.1111/ped.14912DOI Listing
July 2021

Changes in childhood vaccination during the coronavirus disease 2019 pandemic in Japan.

Vaccine 2021 06 21;39(29):4006-4012. Epub 2021 May 21.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan. Electronic address:

Background: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected daily life. COVID-19 often causes asymptomatic or mild disease in children; however, delayed routine childhood immunization is a concern, as it could increase the risk of vaccine-preventable disease. No study has evaluated the status of childhood vaccinations in Japan during the COVID-19 pandemic.

Methods: This retrospective observational study evaluated the number of vaccine doses administered to children in 4 Japanese cities (2 cities in the Tokyo metropolitan area and 2 cities far from Tokyo) during the period from 2016 to 2020. Vaccine doses administered between January and September 2020 during the COVID-19 pandemic were compared, by month, with those given during 2016-2019. Age-stratified demographic data were collected to determine whether factors other than change in the child population over time affected vaccination trends.

Results: In all cities the decrease in vaccine doses administered was most apparent in March and April 2020, i.e., just before or coincident with the declaration of a nationwide COVID-19 emergency on April 7, 2020. The decrease started as early as February in the Tokyo metropolitan area. As child age increased, the decrease became more apparent. Before the lift of national emergency on May 25, catch-up of the vaccination was observed in all age groups in all cities. Vaccine doses persistently increased in older age groups but not in infants. The overall vaccination trends did not differ significantly among the 4 cities.

Conclusions: The COVID-19 pandemic significantly affected routine childhood immunization in Japan. Thus, a nationwide electronic surveillance system and announcements for guardians to encourage timely routine immunization are warranted.
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http://dx.doi.org/10.1016/j.vaccine.2021.05.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139263PMC
June 2021

Changes and remaining challenges for the Japanese immunization program: Closing the vaccine gap.

Vaccine 2021 05 28;39(22):3018-3024. Epub 2021 Apr 28.

Kawasaki City Institute for Public Health, 3-25-13 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan.

The Japanese immunization program has made considerable progress since 2009: several new vaccines have been introduced and most are included in the National Immunization Program (NIP). In October 2020, the Japanese law on immunization was revised, which resulted in a few laudable achievements. First, rotavirus vaccines were added to the NIP, 10 years after their introduction, and noteworthy studies of vaccine effectiveness and the incidence of intussusception in Japanese children were published. Second, rules on vaccine intervals-which had been a longstanding concern-were withdrawn. In addition to this revision of the law, the Japanese version of the Vaccine Information Statement (VIS) was released by the Japan Pediatric Society in 2018. The VIS provides useful caregiver information on general immunization concepts and individual vaccines. Further challenges for the Japanese immunization program include (1) administering a booster dose of pertussis-containing vaccine to preschool children or teenagers, (2) reestablishing the active recommendation for human papilloma virus vaccines, (3) adding the mumps and influenza vaccines to the NIP, and (4) ensuring optimal dosing of seasonal influenza vaccines. During the current coronavirus disease 2019 (COVID-19) pandemic, vaccination rates among children have been decreasing in many countries. In Japan, vaccination rates have been stable in infants, but declining among toddlers and school-aged children, despite public awareness of the need for timely administration of vaccines during the pandemic. Clearly, further action is needed if we are to adequately protect children living in Japan from vaccine-preventable diseases.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.023DOI Listing
May 2021

PCR detection rates for serum and cerebrospinal fluid from neonates and young infants infected with human parechovirus 3 and enteroviruses.

J Clin Virol 2021 02 15;135:104736. Epub 2021 Jan 15.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Background: Human parechovirus 3 (HPeV-3) and enteroviruses (EV) are commonly detected viruses in febrile neonates and young infants and are usually diagnosed by PCR. However, in this population, data on detection rates for samples from different anatomical sites are limited.

Objectives: To determine PCR detection rates for HPeV-3 and EVs in serum and cerebrospinal fluid (CSF) samples from febrile neonates and young infants.

Study Design: This prospective study identified viruses in serum and CSF samples collected from febrile neonates and young infants (age <4 months) in Niigata, Japan, during 2014-2018. HPeV-3 or EV infection was defined as a positive quantitative real-time PCR result for the virus in serum or CSF. Genotypes were identified by sequence analyses of the viral protein 1 region.

Results: Among 216 patients, we identified 56 HPeV-3-infected (26 %) and 48 EV-infected patients (22 %). All (56/56; 100 %) HPeV-3-infected patients had a positive PCR result for serum, and 49/56 (88 %) had a positive result for CSF. In EV-infected patients, 40/48 (83 %) were positive for serum, and 34/48 (71 %) were positive for CSF, and 22/48 (46 %) were positive for serum (n = 14) or CSF (n = 8). If only a CSF sample had been obtained, 7 (12 %) HPeV-3 infections and 14 (29 %) EV infections would have been undiagnosed. Detection rates in serum and CSF differed by genotype in EV-infected patients.

Conclusions: Viral RNA detection rates differed between serum and CSF in HPeV-3- and EV-infected neonates/infants. Combined evaluation of serum and CSF samples is important for accurate viral diagnosis in this population.
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http://dx.doi.org/10.1016/j.jcv.2021.104736DOI Listing
February 2021

Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion Associated with Rhinovirus.

Pediatr Infect Dis J 2021 03;40(3):e122-e125

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

A 2-year-old girl with fever and seizures was diagnosed as having clinically mild encephalitis/encephalopathy with a reversible splenial lesion, as indicated by magnetic resonance imaging. Virologic analysis identified human rhinovirus A49 in her serum. Although human rhinovirus rarely involves the central nervous system, such involvement could result in mild encephalitis/encephalopathy with a reversible splenial lesion.
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http://dx.doi.org/10.1097/INF.0000000000002995DOI Listing
March 2021

Acute heart failure due to dilated cardiomyopathy exacerbated by systemic parechovirus A1 infection in an infant.

Int J Infect Dis 2021 Mar 13;104:273-275. Epub 2021 Jan 13.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Parechovirus A1 (PeV-A1) often causes mild respiratory or gastrointestinal disease. Herein we report a case of acute heart failure due to dilated cardiomyopathy exacerbated by acute PeV-A1 infection in a 10-month-old infant. He was brought to our hospital with acute respiratory distress and compensated shock. Echocardiogram showed a dilated left ventricle and severe mitral regurgitation, consistent with dilated cardiomyopathy. PeV-A1 infection was confirmed by (1) positive PCR test results for PeV-A in multiple anatomical sites, including blood, stool, and throat, (2) the genetic sequence of viral protein, and (3) an increase in paired serum PeV-A1-specific neutralizing antibody titers. A few, scattered case reports in infants and young children also indicate the association between myocarditis and/or dilated cardiomyopathy and PeV-A1 infection. In conclusion, PeV-A1 infection could be associated with exacerbation of myocardial diseases in infants and young children; thus PeV-A1 needs to be evaluated as a viral cause of such a condition.
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http://dx.doi.org/10.1016/j.ijid.2021.01.021DOI Listing
March 2021

Pott's puffy tumour: a rare and life-threatening disease.

Lancet Infect Dis 2020 12 25;20(12):1482. Epub 2020 Nov 25.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30684-8DOI Listing
December 2020

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

Vaccine 2020 11 1;38(50):8049-8054. Epub 2020 Nov 1.

The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan; Division of Basic Nursing, Fukuoka Nursing College, Fukuoka, Japan.

Background: Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan.

Methods: This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups.

Results: We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01).

Conclusion: The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.049DOI Listing
November 2020

Fatal Progressive Meningoencephalitis Diagnosed in Two Members of a Family With X-Linked Agammaglobulinemia.

Front Pediatr 2020 18;8:579. Epub 2020 Sep 18.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Chronic enteroviral meningoencephalitis is a well-known complication in patients with X-linked agammaglobulinemia (XLA). However, progressive neurodegenerative disorders or chronic neuroinflammatory diseases with no causative microorganisms have been recognized as rare central nervous system (CNS) complications in XLA. We herein report a family in which two of three members with XLA had developed progressive meningoencephalitis with an unknown etiology. A 15-month-old male infant presented with left-sided ptosis. Initially, the family denied any family history of inherited diseases, but later disclosed a family history of agammaglobulinemia previously diagnosed in two family members. In the early 1980s, one of the elder brothers of the index patient's mother who had been treated with intramuscular immunoglobulin [or later intravenous immunoglobulin (IVIG)] for agammaglobulinemia deceased at 10 years of age after showing progressive neurological deterioration during the last several years of his life. The index patient was diagnosed with XLA caused by Bruton tyrosine kinase deficiency (654delG; Val219Leufs9), and chronic meningoencephalitis with an unknown infectious etiology. Magnetic resonance imaging of the brain demonstrated inflammatory changes in the basal ganglia, hypothalamus, midbrain, and pons, with multiple nodular lesions with ring enhancement, which showed impressive amelioration after the initiation of IVIG replacement therapy. Pleocytosis, which was characterized by an increase in CD4-positive and CD8-positive T cells expressing an activation marker and an elevation in inflammatory cytokines in the cerebrospinal fluid, was identified. No microorganism was identified as a cause of CNS complications. He thereafter developed brain infarction at 19 months of age and fatal status epilepticus at 5 years of age, despite regular IVIG with high trough levels and regular intraventricular immunoglobulin administration. The etiology of this rare CNS complication in XLA is currently unknown. Previous studies have suggested a possible association of IVIG, which was clearly denied in our index case because of the demonstration of his neurological disorder at presentation. In the future, extensive and unbiased molecular methods to detect causative microorganisms, as well as to investigate the possible role of autoimmunity are needed to clarify the etiology of CNS complications.
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http://dx.doi.org/10.3389/fped.2020.00579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530192PMC
September 2020

Comparison of immunization systems in Japan and the United States - What can be learned?

Vaccine 2020 10 29;38(46):7401-7408. Epub 2020 Sep 29.

Vaccine Education Center, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Recently, efforts have been made to fill a so-called "vaccine gap" between Japan and other countries; however, more work remains. Concerns about adverse events following immunization (AEFI) resulted in an historically passive approach to policy making in the National Immunization Program (NIP). For example, reports of AEFI following human papillomavirus vaccine (HPVV) in 2013 led the Japanese government to withdraw its proactive recommendations, resulting in a sharp drop in HPVV coverage rate to less than 1.0%. In this report, we review key historical incidents that led to the current immunization system in Japan, compare it to that in the United States, and discuss strategies for improving the Japanese immunization system. By strengthening existing policies and programs, such as National Immunization Technical Advisory Groups and AEFI reporting, compensation laws, and immunization education, the remaining vaccine gap in Japan could be filled.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.028DOI Listing
October 2020

Outbreak of Enterovirus D68 Among Children in Japan-Worldwide Circulation of Enterovirus D68 Clade B3 in 2018.

Pediatr Infect Dis J 2021 01;40(1):6-10

From the Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences.

Background: Enterovirus D68 (EV-D68) causes asthma-like respiratory infection in children. Several EV-D68 outbreaks have been reported worldwide since the largest outbreak occurred in the United States in 2014. We experienced an accumulation of pediatric cases with asthma-like respiratory illness in Niigata, Japan, in 2018.

Study Design: To determine whether EV-D68 was responsible for the case accumulation, this prospective observational study evaluated children hospitalized in 1 of 8 hospitals with asthma-like respiratory illness in Niigata, Japan, during October and November 2018. Diagnoses were made by EV-D68-specific RT-PCR using nasopharyngeal samples. The clade was identified by sequence analyses, and a phylogenetic tree was created. To evaluate seasonal variation, data from pediatric cases with asthma-like respiratory illness in 2018 were retrospectively analyzed.

Results: In 2018, 114 children were hospitalized with asthma-like respiratory illness in October and November, and 47 nasopharyngeal samples were collected. EV-D68 was detected in 22/47 (47%) patients during the study period. The phylogenetic tree revealed that all strains belonged to the clade B3 branch, which has been detected worldwide every 2 years since 2014.

Conclusions: EV-D68 was the associated pathogen for asthma-like respiratory illness in children in Japan in 2018. Clade B3, the dominant clade in outbreaks worldwide, was responsible for the outbreak. Detection and detailed virologic analysis of EV-D68 is important as part of worldwide surveillance, as it will aid in understanding the epidemiologic characteristics of EV-D68 infection.
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http://dx.doi.org/10.1097/INF.0000000000002889DOI Listing
January 2021

Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency.

Clin Pediatr Endocrinol 2020 11;29(3):105-110. Epub 2020 Jul 11.

Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.

Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.
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http://dx.doi.org/10.1297/cpe.29.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348630PMC
July 2020

Development and characterisation of NKp44-based chimeric antigen receptors that confer T cells with NK cell-like specificity.

Clin Transl Immunology 2020 8;9(7):e1147. Epub 2020 Jul 8.

Department of Pediatrics Niigata University Graduate School of Medical and Dental Sciences Niigata Japan.

Objectives: One of the reasons as to why chimeric antigen receptors (CAR)-T cell therapy for malignancies other than CD19- or BCMA-positive tumors has yet to produce remarkable progress is the paucity of targetable antigens. NKp44 is only expressed by activated natural killer cells and detects a variety of transformed cells, while it reportedly does not react with normal tissues. The aim of this study is to develop CAR-T cell that can target multiple types of tumor cells.

Methods: We created a series of novel CAR constructs in first-generation (1G) and second-generation (2G) CAR format with the extracellular immunoglobulin-like domain of NKp44 (NKp44-CAR).

Results: Transduction of the best 1G construct into human primary T cells led to specific cytotoxic effects and cytokine secretion upon encountering multiple types of neoplastic cells including AML, T-ALL and childhood solid tumors. Replacement of the extracellular hinge domain of NKp44 with that of CD8α resulted in diminished CAR function. The 1G NKp44-CAR-T cells exhibited significantly better tumor control in long-term co-culture assays compared with activated NK cells, as well as with NK cells transduced with identical NKp44-CAR. T cells transduced with the best 2G-CAR construct with 4-1BB co-stimulatory domain proliferated at significantly higher levels upon single antigen exposure and showed significantly better tumor control compared with the 1G-CAR and 2G-CAR with CD28 co-stimulatory domain.

Conclusions: NKp44-based CAR endows T cells with NK cell-like anti-tumor specificity. The CAR gene created in this study will be useful for the development of novel gene-modified T-cell immunotherapy.
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http://dx.doi.org/10.1002/cti2.1147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341825PMC
July 2020

Skin thickness in neonates: Implications for intradermal vaccination.

Vaccine 2020 07 10;38(35):5659-5664. Epub 2020 Jul 10.

Department of Pediatrics, Saiseikai Niigata Hospital, Niigata, Japan.

Introduction: Intradermal (ID) injection is an alternate route that enhances vaccine immunogenicity and decreases vaccine dose. Regular immunization usually starts at age 2 months, and the limited immune capacity of neonates and young infants makes them vulnerable to infection. Successful ID vaccine delivery in this population requires knowledge of skin thickness. Although skin thickness has been evaluated in infants aged 2 months or older, no comparable data are available for neonates, including preterm neonates.

Methods: This prospective observational study used ultrasonography to assess skin thickness in 70 neonates (35 full-term and 35 preterm neonates) at deltoid, suprascapular, and thigh sites. The measurements were compared in relation to anatomical site, between full-term and preterm infants, and with skin thickness values for children aged 2 months or older, which were collected in our previous study using the same measurement technique.

Results: In full-term neonates, skin was significantly thicker at the suprascapular site than at the deltoid and thigh sites (P < 0.05); in preterm neonates, skin was significantly thicker at the suprascapular site than at the thigh site (P < 0.05). Skin thickness values at all three sites were significantly lower in preterm neonates than in full-term neonates (P < 0.05). As compared with skin thickness values for infants aged 2 months, values for full-term neonates were significantly lower for the deltoid and suprascapular sites (P < 0.001).

Conclusions: Skin thickness values for neonates were affected by prematurity and were significantly lower than those for infants aged 2 months. These findings are important in the design of ID injection devices for neonates and young infants.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.061DOI Listing
July 2020

Changes in laboratory findings in Parechovirus-A infection in nine neonates and infants.

Pediatr Int 2020 06;62(6):755-758

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

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http://dx.doi.org/10.1111/ped.14197DOI Listing
June 2020

Serostatus following polio-containing vaccination before and after liver transplantation.

Pediatr Transplant 2020 09 18;24(6):e13766. Epub 2020 Jun 18.

Division of Infectious Diseases, Department of Medical Subspecialties, National Center for Child Health and Development, Tokyo, Japan.

Background: The strategy to eradicate polio is based on preventing infection by immunizing all children until the world is polio-free. However, data regarding efficacy of polio-containing vaccination in immunocompromised patients such as LT recipients are limited.

Methods: We conducted an observational study at the largest pediatric transplant center in Japan from January 2011 to January 2015. LT recipients were enrolled after transplantation, and those who had completed the Japanese polio vaccination program were eligible for the study. Patients' demographics were collected from their medical records. Antibody titers against poliovirus serotypes 1-3 were measured using the neutralization test at the routine follow-up visits after enrollment. Factors associated with seropositivity against each type of poliovirus were evaluated.

Results: Sixty-four patients who had received the complete polio vaccination series were enrolled in the study. Of these, 37 patients had received all series of polio-containing vaccination before LT. Median age of the patients was 75 months. Their underlying diseases included the following: 40 (63%) with cholestatic liver diseases and 11 (17%) with metabolic disorders. After a median interval of 43 months after LT, seropositivity rates against poliovirus 1, 2, and 3 were 93.8% (60/64), 92.2% (59/64), and 54.7% (35/64), respectively. Among 32 patients who had received only oral polio vaccine (OPV), seropositivity against poliovirus 3 was particularly low (25.0%). No factors associated with seropositivity against each type of poliovirus were identified.

Conclusions: In the LT recipients, seropositivity for poliovirus 3 was low, suggesting a need for additional inactivated polio-containing vaccination after LT, especially for patients who had received only OPV.
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http://dx.doi.org/10.1111/petr.13766DOI Listing
September 2020

Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish.

IBRO Rep 2020 Dec 1;9:1-8. Epub 2020 Jun 1.

Department of Neuroscience of Disease, Center for Transdisciplinary Research, Niigata University, Niigata, Japan.

is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, < 0.001 and < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, < 0.001 and < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction ( < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.
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http://dx.doi.org/10.1016/j.ibror.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283103PMC
December 2020

Improving Hand Hygiene Adherence in Healthcare Workers Before Patient Contact: A Multimodal Intervention in Four Tertiary Care Hospitals in Japan.

J Hosp Med 2020 05 27;15(5):262-267. Epub 2020 Apr 27.

Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan.

Background: Hand hygiene is key to preventing healthcare-associated infection and the spread of respiratory viruses like the novel coronavirus that causes COVID-19. Unfortunately, hand hygiene adherence of healthcare workers (HCWs) in Japan is suboptimal according to previous studies.

Objectives: Our objectives were to evaluate hand hygiene adherence among physicians and nurses before touching hospitalized patients and to evaluate changes in hand hygiene adherence after a multimodal intervention was implemented.

Design, Setting, And Participants: We conducted a pre- and postintervention study with HCWs at four tertiary hospitals in Niigata, Japan. Hand hygiene observations were conducted from June to August 2018 (preintervention) and February to March 2019 (postintervention).

Intervention: The multimodal hand hygiene intervention recommended by the World Health Organization was tailored to each hospital and implemented from September 2018 to February 2019.

Main Outcomes And Measures: We observed hand hygiene adherence before touching patients in each hospital and compared rates before and after intervention. Intervention components were also evaluated.

Results: There were 2,018 patient observations preintervention and 1,630 postintervention. Overall, hand hygiene adherence improved from 453 of 2,018 preintervention observations (22.4%) to 548 of 1,630 postintervention observations (33.6%; P < .001). Rates improved more among nurses (13.9 percentage points) than among doctors (5.7 percentage points). Improvement varied among the hospitals: Hospital B (18.4 percentage points) was highest, followed by Hospitals D (11.4 percentage points), C (11.3 percentage points), and Hospital A (6.5 percentage points).

Conclusions: A multimodal intervention improved hand hygiene adherence rates in physicians and nurses in Niigata, Japan; however, further improvement is necessary. Given the current suboptimal hand hygiene adherence rates in Japanese hospitals, the spread of COVID-19 within the hospital setting is a concern.
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http://dx.doi.org/10.12788/jhm.3446DOI Listing
May 2020

Innate Immune Responses in Serum and Cerebrospinal Fluid From Neonates and Infants Infected With Parechovirus-A3 or Enteroviruses.

J Infect Dis 2020 07;222(4):681-689

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Parechovirus (PeV)-A3 and enteroviruses (EV) are the most common viruses causing sepsis and meningoencephalitis in neonates and young infants. Clinical manifestations of PeV-A3 infection are more severe than those of EV infection, and no pleocytosis with a positive polymerase chain reaction (PCR) result for PeV-A3 in cerebrospinal fluid (CSF) are characteristic findings. We hypothesized that innate immune responses to PeV-A3 and EV are distinct in serum and CSF.

Methods: We evaluated 22 cytokines/chemokines in serum and CSF from PeV-A3- or EV-infected patients younger than 4 months in Niigata, Japan, from 2015 through 2018. Infection was diagnosed with real-time PCR followed by sequencing. Febrile neonates and infants with sepsis-like syndrome who had negative bacterial culture and viral PCR for both PeV-A and EV were also included (non-PeV-A/EV patients).

Results: Among 192 febrile patients, we evaluated 16 PeV-A3-infected, 15 EV-infected, and 8 non-PeV-A/EV patients. Serum pro-/anti-inflammatory cytokine/chemokine levels were higher in PeV-A3-infected patients than in EV-infected patients (P < .02). Although most cytokine/chemokine were elevated in CSF from EV-infected patients, levels were low or undetectable in PeV-A3-infected and non-PeV-A/EV patients (P < .001).

Conclusions: Distinct cytokine/chemokine patterns in serum and CSF may explain the different clinical manifestations of PeV-A3-infected and EV-infected neonates and young infants.
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http://dx.doi.org/10.1093/infdis/jiaa131DOI Listing
July 2020

Parechovirus-A3 encephalitis presenting with focal seizure mimicking herpes simplex virus infection.

J Infect Chemother 2020 Jul 20;26(7):736-740. Epub 2020 Mar 20.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. Electronic address:

Background: Febrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis.

Cases: We have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language.

Conclusions: PeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.
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http://dx.doi.org/10.1016/j.jiac.2020.02.003DOI Listing
July 2020

Epidemic of influenza A(H1N1)pdm09 analyzed by full genome sequences and the first case of oseltamivir-resistant strain in Myanmar 2017.

PLoS One 2020 4;15(3):e0229601. Epub 2020 Mar 4.

National Health Laboratory, Department of Medical Services, Ministry of Health and Sports, Yangon, Yangon Region, Myanmar.

A community outbreak of human influenza A(H1N1)pdm09 virus strains was observed in Myanmar in 2017. We investigated the circulation patterns, antigenicity, and drug resistance of 2017 influenza A(H1N1)pdm09 viruses from Myanmar and characterized the full genome of influenza virus strains in Myanmar from in-patients and out-patients to assess the pathogenicity of the viruses. Nasopharyngeal swabs were collected from out-patients and in-patients with acute respiratory tract infections in Yangon and Pyinmana City in Myanmar during January-December 2017. A total of 215 out-patients and 18 in-patients infected with A(H1N1)pdm09 were detected by virus isolation and real-time RT-PCR. Among the positive patients, 90.6% were less than 14 years old. Hemagglutination inhibition (HI) antibody titers against A(H1N1)pdm09 viruses in Myanmar were similar to the recommended Japanese influenza vaccine strain for 2017-2018 seasons (A/Singapore/GP1908/2015) and WHO recommended 2017 southern hemisphere vaccine component (A/Michigan/45/2015). Phylogenetic analysis of the hemagglutinin sequence showed that the Myanmar strains belonged to the genetic subclade 6B.1, possessing mutations of S162N and S164T at potential antigenic sites. However, the amino acid mutation at position 222, which may enhance the severity of disease and mortality, was not found. One case with no prior history of oseltamivir treatment possessed H275Y mutated virus in neuraminidase (NA), which confers resistance to oseltamivir and peramivir with elevated IC50 values. The full genome sequence of Myanmar strains showed no difference between samples from in-patients and out-patients, suggesting no additional viral mutations associated with patient severity. Several amino acid changes were observed in PB2, PB1, and M2 of Myanmar strains when compared to the vaccine strain and other Asian strains. However, no mutations associated with pathogenicity were found in the Myanmar strains, suggesting that viral factors cannot explain the underlying reasons of the massive outbreak in Myanmar. This study reported the first detection of an oseltamivir-resistant influenza virus in Myanmar, highlighting the importance of continuous antiviral monitoring and genetic characterization of the influenza virus in Myanmar.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229601PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055873PMC
June 2020

Novel scoring system for differentiating parechovirus-A3 and enterovirus infection in neonates and young infants.

J Clin Virol 2020 03 7;124:104256. Epub 2020 Jan 7.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. Electronic address:

Background: Parechovirus-A3 (PeV-A3) and the enteroviruses (EVs) are the most common viral pathogens responsible for sepsis and meningoencephalitis in neonates and young infants; however, differences in the clinical presentations of two infections are not well described.

Objectives: To describe the clinical presentations of PeV-A3- and EVs-related diseases and develop a novel scoring system to differentiate two diseases.

Study Design: This prospective study used real-time PCR and genetic sequencing to evaluate viral etiologies of febrile neonates and infants <4 months with suspected sepsis or meningoencephalitis in Niigata area, Japan, in 2014-2016. The clinical manifestations of PeV-A3- and EVs-infected patients were compared, and a novel scoring system was developed after identifying the most distinguishable clinical findings, followed by the external cohort validation.

Results: In 210 patients evaluated, we identified 56 PeV-A3-infected (27%) and 43 EVs-infected (20%) patients. The following clinical manifestations were significant in PeV-A3-infected patients, as compared with EVs-infected patients; a higher body temperature (38.9°C vs. 38.5°C, P < .01) and heart rate (181/min vs. 168/min, P = .01), cold extremities (72% vs. 34%, P < .01) and skin mottling (65% vs. 23%, P < .01), lower white blood cell count (5,200/μL vs. 8,900/μL, P < .01) and incidence of cerebrospinal fluid (CSF) pleocytosis (2% vs. 63%, P < .01). Using some of these significant findings, the scoring system successfully distinguished the diseases (accuracy: 86% and 83% for the derivative and external validation cohorts, respectively).

Conclusions: We found significant clinical manifestations in PeV-A3-infected patients compared to EVs-infected patients. The scoring system may be helpful to distinguish two infections, especially at onset of outbreak.
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http://dx.doi.org/10.1016/j.jcv.2019.104256DOI Listing
March 2020

Spontaneous remission of infant acute myeloid leukemia with a novel four-way translocation.

Pediatr Blood Cancer 2020 02 13;67(2):e28052. Epub 2019 Nov 13.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

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http://dx.doi.org/10.1002/pbc.28052DOI Listing
February 2020

Clinical Characteristics of Saffold Virus Infection in Children.

Pediatr Infect Dis J 2019 08;38(8):781-785

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Background: Saffold virus (SAFV) is a novel human cardiovirus that was identified in 2007. Recently, SAFV has been isolated from nasal and stool specimens of infants presenting with respiratory and gastrointestinal symptoms and from cerebrospinal fluid (CSF) specimens of children with central nervous system infection. However, little is known regarding clinical characteristics of SAFV in children.

Methods: We reviewed 5412 specimens from the database of the infectious agents surveillance system in Niigata prefecture, Japan, between January 2006 and December 2013, and identified SAFV-infected patients. Subsequently, we retrospectively reviewed their medical records and evaluated their clinical characteristics.

Results: We identified 9 SAFV-infected patients (median age: 5 years; range: 2-16 years). Seven patients were diagnosed with pharyngitis, one with meningitis and one with fever of unknown origin. Dominant symptoms were high fever, appetite loss and headache. The median duration of the fevers was 2 days in patients with pharyngitis; however, the patient with meningitis remained febrile for 5 days. All blood tests available in this case series revealed leukocytosis with a predominance of neutrophils. CSF profiles showed mild lymphocytic pleocytosis. All patients recovered fully without complications.

Conclusions: A few clinical characteristics of SAFV infection were clarified, including high fever of short duration in patients with pharyngitis, and neutrophil-dominant leukocytosis. The clinical course and CSF profiles of a case of meningitis were similar to those of other aseptic meningitis. SAFV needs to be included in the differential diagnosis of pharyngitis or meningitis when commonly identified viruses are not identified in such patients.
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http://dx.doi.org/10.1097/INF.0000000000002298DOI Listing
August 2019

Aphthous lesions on the soft palate in a neonate.

Pediatr Int 2019 Jan;61(1):107-108

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan.

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http://dx.doi.org/10.1111/ped.13723DOI Listing
January 2019

Dynamic QT Changes in Long QT Syndrome Type 8.

Circ J 2019 06 22;83(7):1614. Epub 2018 Dec 22.

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science.

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http://dx.doi.org/10.1253/circj.CJ-18-0984DOI Listing
June 2019

Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection.

Vaccine 2019 01 13;37(1):160-168. Epub 2018 Nov 13.

Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Research Centre for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Vaccination is an effective strategy to prevent pneumococcal diseases. Currently, licensed vaccines include the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV), which target some of the most common of the 94 serotypes of S. pneumoniae based on their capsular composition. However, it has been reported that PPSV is not effective in children aged less than 2 years old and PCV induces serotype replacement, which means that the pneumococcal population has changed following widespread introduction of these vaccines, and the non-vaccine serotypes have increased in being the cause of invasive pneumococcal disease. Therefore, it is important that there is development of novel pneumococcal vaccines to either replace or complement current polysaccharide-based vaccines. Our previous study suggested that S. pneumoniae releases elongation factor Tu (EF-Tu) through autolysis followed by the induction of proinflammatory cytokines in macrophages via toll-like receptor 4, that may contribute to the development of pneumococcal diseases. In this study, we investigated the expression of EF-Tu in various S. pneumoniae strains and whether EF-Tu could be an antigen candidate for serotype-independent vaccine against pneumococcal infection. Western blotting and flow cytometry analysis revealed that EF-Tu is a common factor expressed on the surface of all pneumococcal strains tested, as well as intracellularly. In addition, we demonstrate that immunization with recombinant (r) EF-Tu induced the production of inflammatory cytokines and the IgG1 and IgG2a antibodies in mice, and increased the CD4 T-cells proportion in splenocytes. We also reveal that anti-EF-Tu serum increased the phagocytic activity of mouse peritoneal macrophages against S. pneumoniae infection, independent of their serotypes. Finally, our results indicate that mice immunized with rEF-Tu were significantly and non-specifically protected against lethal challenges with S. pneumoniae serotypes (2 and 15A). Therefore, pneumococcal EF-Tu could be an antigen candidate for the serotype-independent vaccine against pneumococcal infection.
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http://dx.doi.org/10.1016/j.vaccine.2018.11.015DOI Listing
January 2019

Persistence of High Neutralizing Antibody Titers After Neonatal and Early Infantile Infection with Parechovirus-A3.

Pediatr Infect Dis J 2019 07;38(7):e159-e161

From the Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences.

This 3-year follow-up study evaluated neutralizing antibody titers (NATs) against parechovirus-A3 (PeV-A3) in neonates and young infants who developed PeV-A3 infection. All children had low NATs at disease onset and high NATs after infection during infancy. At age 3 years, all 16 patients tested had high NATs (≥1:512) against PeV-A3 indicating that specific PeV-A3 NATs persist into childhood.
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http://dx.doi.org/10.1097/INF.0000000000002245DOI Listing
July 2019

Neuropsychiatric Disorder Associated with Group G Infection.

Case Rep Pediatr 2018 23;2018:6047318. Epub 2018 Sep 23.

Department of Pediatrics, Niigata University, Niigata, Japan.

Immune-mediated central nervous system manifestations of group A -hemolytic (GABHS) infection include Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)-which includes tic and obsessive compulsive disorders-and a variety of neurobehavioral disorders. We report a case of subspecies (group G ) (GGS) infection associated with involuntary movements, complex tics, and emotional lability in an 11-year-old Japanese girl. Serum IgM and IgG antibodies to lysoganglioside were positive, and she responded rapidly to intravenous immunoglobulin treatment. Neuropsychiatric disorder associated with GGS infection was ultimately diagnosed. The present findings suggest that neuropsychiatric disorders can result from GGS infection and that the pathogenic mechanism is similar to that of GABHS infection. Future large-scale studies should examine the relation between GGS infection and onset of neuropsychiatric disorder.
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http://dx.doi.org/10.1155/2018/6047318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174767PMC
September 2018

The association of epileptic focus estimated by magnetoencephalography with cognitive function in non-lesional epilepsy with continuous spikes and waves during slow wave sleep (ECSWS) children.

Brain Dev 2019 Feb 17;41(2):163-172. Epub 2018 Oct 17.

Division of Child Neurology, Nishi-Niigata Chuo National Hospital, Japan.

Objective: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome.

Methods: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis.

Results: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110 months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156 months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (β = 14.7, p = 0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (β = 17.48, p = 0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis.

Conclusion: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences.
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http://dx.doi.org/10.1016/j.braindev.2018.09.005DOI Listing
February 2019