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Mihoko Furuichi,1 Kaoru Goto,2 Nobuyuki Tetsuka,3 Katsushi Ishida,4 Isao Miyairi,3 Yoshiaki Cho,5 Masashi Kasai,6 Yukiya Kurahashi,7 Hideki Akeda,7 Yuho Horikoshi1 1Division of Infectious Diseases, Department of Pediatrics, 2Division of Microbiology, Department of Clinical Laboratory, Tokyo Metropolitan Children’s Medical Center, 3Division of Infectious Diseases, Department of Pediatrics, 4Division of Microbiology, Department of Clinical Laboratory, National Center for Child Health and Development, Tokyo, 5Department of Pediatrics, 6Division of Pediatric Critical Care Medicine and Infectious Disease, Nagano Children’s Hospital, Nagano, 7Department of General Pediatrics, Okinawa Prefectural Nanbu Medical Center & Children’s Medical Center, Okinawa, Japan Abstract: Group B streptococcus (GBS) is an important cause of serious bacterial infections (SBIs) in infants. Non-penicillin-susceptible GBS strains have been reported among adults, but little is known among children. We collected GBS isolates from 4 children’s hospitals in Japan, and performed serotyping of GBS strains and reviewed penicillin minimum inhibitory concentrations of GBS strains from both sterile and non-sterile sites. Our examination revealed 235 isolates including 41 isolates from SBIs and 194 isolates from colonization. Nine cases of GBS SBIs (21.9%) were early-onset, 19 (46.3%) were late-onset, and 13 (31.7%) were ultra-late-onset. Non-penicillin-susceptible GBS strains were not detected among either isolates. Serotypes Ia, Ib, and III were predominant among SBIs. In conclusion, at this time, we have no non-penicillin-susceptible GBS strains in Japanese children. Penicillin susceptibility should continue to be monitored carefully in each geographic area. Keywords: GBS, serotypes, penicillin, MIC, children

Background: To address antibiotic overuse, the Japanese government implemented a novel financial incentive policy in 2018. The policy enables eligible healthcare facilities to claim 800 JPY (≈5.7 USD) per case wherein a rationale to not prescribe antibiotics is offered to children aged <3 years with acute upper respiratory tract infections or gastroenteritis. Although the short-term effect of this policy was observed in our previous study, its long-term effects have not been evaluated nationwide., Methods: We conducted a quasi-experimental study using a staggered difference-in-differences design with propensity score matching. Data from 165,113 children born between April 2017 and March 2019 were extracted from two nationwide administrative databases. The study tracked these children until May 2022, comparing those exposed to the policy with those who were not., Results: The introduction of financial incentives led to a 44.9% reduction (95%CI, 41.1% to 47.7%) in total antibiotic prescriptions within the first month and 19.5% reduction (95%CI, 8.7% to 29.1%) over 48 months. Broad-spectrum antibiotic use also decreased by 24.4% (95%CI, 14.0% to 33.6%) over the same period. The policy did not result in increased hospitalizations, after-hours visits, or healthcare costs, but was associated with a slight increase in the number of office visits. A dose-response relationship was observed, with reductions in antibiotic use leveling off after approximately five incentives., Conclusions: Financial incentives effectively reduced antibiotic prescriptions in children without adverse health outcomes, demonstrating sustained benefits over four years. This antimicrobial stewardship intervention offers a scalable model for other countries aiming to curb antibiotic overuse and combat antimicrobial resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) and influenza virus are major viral etiologies of pediatric lower respiratory tract infection, but comparative data on inpatient burden are lacking., Methods: Using a large-scale health claims database in Japan, we identified patients under 5 years of age with a confirmed RSV or influenza diagnosis as an outpatient or inpatient between 2011 and 2022. Hospitalization rate, inpatient characteristics, various in-hospital outcomes/complications, and healthcare resource utilization were described., Results: A total of 176,911 RSV-confirmed outpatients, 153,383 influenza-confirmed outpatients, 90,413 RSV-confirmed hospitalizations, and 11,186 influenza-confirmed hospitalizations were identified. Among outpatients, 24.7% of RSV infection and 2.8% of influenza cases required hospitalization within 1 week. There was no co-morbidities/prematurity for 95.0% of RSV hospitalizations and 96.5% of influenza hospitalizations. Proportions of in-hospital outcomes/complications were (RSV infection vs. influenza): oxygen use 47.6% vs. 14.8%, mechanical ventilation 2.1% vs. 0.7%, pneumonia 33.6% vs. 12.8%, otitis media 7.7% vs. 2.3%, febrile seizure 1.5% vs. 34.4%, encephalitis/encephalopathy 0.1% vs. 0.5%, myocarditis < 0.1% vs. 0.6%, antibiotics prescription 48.0% vs. 24.4%. The mean inpatient stay was 6.1 vs. 4.3 days at direct medical costs of 435,744 vs. 315,809 JPY/patient. These trends held true in age-stratified data. In-hospital death occurred in 31 RSV infection and 6 influenza cases., Conclusions: Although both infections resulted in substantial burden, RSV infection led to more frequent hospitalizations, worse in-hospital outcomes, longer inpatient stays, higher medical costs, and more frequent antibiotics prescription compared to influenza. Most RSV hospitalizations occurred among healthy term children, emphasizing the need for prevention measures in all children., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: A nationwide survey conducted by the Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases in 2020 provided insights into antimicrobial prescription practices among clinic doctors. This study aimed to investigate factors influencing changes in antimicrobial prescriptions post-implementation of the National Action Plan on Antimicrobial Resistance (NAPAR) and doctors' inclination to prescribe antimicrobials for common cold cases., Methods: In September 2020, randomly selected questionnaires were distributed to 3000 community-based medical clinics in Japan. The primary objective was to assess the reduction in antimicrobial prescriptions post-NAPAR implementation. Multivariate linear regression analysis was employed to identify associated factors., Results: Analysis of 632 responses (response rate: 21.1 %) revealed determinants of decreased antimicrobial prescriptions, including familiarity with the Guide to Antimicrobial Stewardship (β = .482, t = 3.177, p = 0.002) and awareness of NAPAR (β = .270, t = 2.301, p = 0.022)., Conclusion: Interventions such as the Guide to Antimicrobial Stewardship may have contributed to the reduction in antimicrobial prescriptions among Japanese physicians. However, targeted strategies are needed to address high-prescription groups. Enhancing awareness and education on appropriate antimicrobial use should be integral components of future initiatives to combat antimicrobial resistance effectively., Competing Interests: Declaration of competing interest Shigefumi Maezaki has received lecture fees from Pfizer Japan Inc., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co. Ltd., Shionogi & Co. Ltd., MSD K.K., KYORIN Pharmaceutical Co. Ltd., and Taisho Toyama Pharmaceutical Co. Ltd. Tetsuya Matsumoto has received lecture fees from MSD K.K., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., and Meiji Seika Pharma Co., Ltd., as well as research funding from Kewpie Corp. Norio Ohmagari, Yoshiaki Gu, Shinichiro Morioka, Shinya Tsuzuki, Hiroshi Soeda, Chikara Nakahama, Naoki Hasegawa, Yumiko Fujitomo, Masayuki Maeda, and Isao Miyairi have declared no conflicts of interest associated with this manuscript., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic posed substantial challenges to healthcare systems. Understanding the responses of pediatric health services is crucial for future pandemic planning and preparedness, yet such data remains limited., Methods: In this retrospective cohort study, we analyzed data from administrative databases developed by Japan Medical Data Center and DeSC Healthcare Inc. The dataset comprised records of 2,612,511 children, totaling 60,224,888 person-months, from January 2020 to May 2022. Multivariate generalized estimation equations were used to examine the incidence rates of COVID-19 and associated health resource use., Results: Our analysis revealed that the incidence rates of COVID-19 gradually increased from Wave I (2.2 cases per 100,000 person-months) to Wave V (177.8cases per 100,000 person-months), with a notable elevation during Wave VI (2367.7 cases per 100,000 person-months). While nucleic acid amplification tests were primarily used during Waves I-V, the use of rapid antigen tests markedly increased in Wave VI. The hospitalization rates increased gradually from 0.2 in Wave I to 10.2 events per 100,000 person-months in Wave VI, and the case-hospitalization risk decreased from 14.9% in Wave II to 0.7% in Wave VI. Additionally, we observed decreasing trends in the use of antibiotics (Wave I, 31.8%; Wave VI, 9.0%), whereas antipyretic use rose from Wave I (56.1%) to Wave VI (86.6%)., Conclusions: Our study highlighted essential changes in the nationwide pediatric healthcare system's response to the COVID-19 pandemic. These findings provide valuable insights into the future pandemic planning and preparedness., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Co-infection with other pathogens can alter the severity and clinical outcomes of viral infections. However, the information regarding viral co-infections in pediatric coronavirus disease 2019 (COVID-19) cases is still limited., Methods: This is a nationwide, retrospective cohort study using the data from the COVID-19 Registry Japan. The pediatric (<18 years), laboratory confirmed, hospitalized COVID-19 patients in the Omicron variant of concern predominant period (January 2022 to January 2024) were included. Co-infection was investigated by multiplex PCR. We compared clinical characteristics, symptoms, severity, and outcomes between children with and without co-infection., Results: Among 245 hospitalized pediatric COVID-19 patients, 78 (31.8 %) had co-infections. The patient backgrounds of the "co-infection" and "SARS-CoV-2 alone" groups were similar, although age distribution was different, with a lower number of patients over 12 years in the co-infection group (n = 2, 2.6 % vs. n = 29, 17.4 %; P < 0.001). Among the patients with co-infection, the most common pathogen was enterovirus/rhinovirus (51.3 %), followed by parainfluenza virus (23.1 %) and adenovirus (12.8 %). Patients with co-infection more commonly had respiratory symptoms, including SpO 2 < 96 %, shortness of breath, runny nose, and wheezing. Requirement of non-invasive oxygen support was higher in the co-infection group (n = 27, 34.6 % vs. n = 28, 16.8 %, P = 0.006). By multivariable logistic regression analysis, co-infection and presence of any comorbidity were identified as significant risk factors for necessity of oxygen therapy (odds ratio [95 % confidence interval] 2.44 [1.29-4.63] and 3.99 [2.07-7.82], respectively)., Conclusions: Viral co-infection may increase the risk of respiratory distress in pediatric COVID-19 patients., Competing Interests: Declaration of competing interest K. Shoji received payment for lectures from bioMérieux Japan, Nippon Becton Dickinson Company, Ltd., Viatris, Inc., Meiji Seika Pharma Co., Ltd., AstraZeneca K.K., Novartis Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Gilead Sciences, Inc. S. Tsuzuki received payment for supervising medical articles from Gilead Sciences, Inc. I. Miyairi received payment for lectures from Astellas Pharma, Sanofi K.K., Pfizer, Inc., Takeda Pharmaceutical Company, Ltd., Biken Group, Shionogi & Company, Ltd., bioMérieux Japan, Gilead Sciences, Inc., Meiji Seika Pharma, KM Biologics, Tanabe-Mitsubishi Pharmaceuticals, and Daiichi Sankyo. The other authors declare that they do not have any conflicts of interest directly associated with the study., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity., Methods: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination., Results: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V max inhibition [V max, inh ] = 100 %; V max  = 0). The estimated parameters of V max,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher., Conclusion: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V max,inh of voriconazole in children with malignancy or inborn errors of immunity., Competing Interests: Declaration of competing interest KS received honoraria for lectures from Viatris, Inc. IM and MK received honoraria from Pfizer for lectures. All the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: Information on the clinical utility of daptomycin in patients with persistent bacteremia and daptomycin's pharmacokinetic data in pediatric patients has been sparse. In addition, reports on the experience of using daptomycin in children undergoing solid organ transplantation have been extremely limited. The authors describe a pediatric case of persistent bacteremia after solid organ transplantation successfully treated by daptomycin. Blood daptomycin concentrations were measured by liquid chromatography-mass spectrometry and pharmacokinetic analysis was performed. We also conducted a literature review on the use of daptomycin in children with persistent bacteremia., Case Report: An eight-year-old girl who underwent small bowel and liver transplantation experienced persistent bacteremia due to Staphylococcus epidermidis. The bacteremia persisted despite standard therapy; however, it finally resolved with the addition of daptomycin. The patient had renal dysfunction and the initial dosing resulted in excessive drug exposure. The dosage was adjusted based on the pharmacokinetic analysis. The dosage of administrated teicoplanin was also adjusted according to trough concentration values. In the literature review, we identified 12 cases of neonates and 24 cases of post-neonatal children with the experience of using daptomycin for persistent bacteremia; however, no solid organ transplant recipient was identified. Similar trends in blood concentrations and dose ratios of teicoplanin and daptomycin were observed over time., Discussion: More information is required regarding the clinical utility and pharmacokinetics of daptomycin in pediatric patients with persistent bacteremia. Referring to the exposure to renally excreted drugs that are routinely measured and pharmacokinetic analysis of daptomycin may be useful in optimizing the dose of daptomycin in special patient populations, including those with renal impairment., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Data on the safety and antibody response of the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in children aged 5-11 years with underlying diseases are limited. Thus, our study aimed to address this gap., Methods: This prospective observational study investigated the antibody titers for SARS-CoV-2 spike protein receptor-binding domain (S-IgG) and nucleocapsid protein (N-IgG) in patients aged 5-11 years with chronic underlying diseases following two doses of BNT162b2. Additionally, a questionnaire was used to assess adverse events (AEs) arising within 7 days after each dose. Data on severe AEs arising within 28 days after each dose were extracted from the patients' electronic medical records., Results: Among 122 patients, 24.6% (30/122) were immunocompromised. Furthermore, 79 patients experienced at least one AE following vaccination, but all recovered without sequelae, including one severe case after the first dose. The seropositivity rate after the second dose was 99.1% (116/117). Excluding 19 N-IgG-positive patients, the geometric mean antibody titer (GMT) was significantly higher in immunocompetent patients than in immunocompromised patients (1496 U/mL [95% confidence interval 1199-1862] vs. 472 U/mL [200-1119], p = 0.035). Additionally, the GMT of S-IgG was higher in N-IgG-positive patients than in N-IgG-negative patients (8203 [5847-11482] U/mL vs. 1127 [855-1486] U/mL, p < 0.001)., Conclusions: BNT162b2 is acceptably safe and immunogenic for children aged 5-11 years with underlying diseases. Although seroconversion was satisfactory in immunocompromised patients, the titers were lower than in immunocompetent patients., Competing Interests: Declaration of competing interest K. Shoji received payment for lectures from bioMérieux Japan, Gilead Sciences, Inc., Viatris, Inc., and Moderna Japan Co., Ltd. C. Ogimi received payment for lectures from Pfizer, AstraZeneca, and bioMérieux Japan. I. Miyairi received payment for lectures from bioMérieux Japan, Gilead Sciences, Inc., Pfizer, AstraZeneca, Sanofi, and Shionogi Pharmaceuticals. All other authors declare that they do not have any potential, perceived, or real conflicts of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

To cultivate specialists in pediatric infectious diseases (ID) in Japan, the Japanese Society for Pediatric Infectious Diseases initiated board certification for pediatric ID in 2017. Previously, in 2014, we had formed a committee for board certification in pediatric ID and discussed the fundamentals of the board certification system, including the goals, requirements for designated training institutions, provisional certification of pediatric ID specialists and eligibility for and content of the board certification examination. After approval from 31 programs, the pediatric ID programs started in 2017 with 8 fellows in 7 programs. The first 6 graduates received board certification in 2020. To date, 61 pediatricians have been board certified as pediatric ID specialists. In parallel, we introduced board certification for pediatricians who work mainly in primary care settings and have a special interest in pediatric ID. This system has certified 338 pediatricians. During and after the development of the programs, we achieved substantial progress in highlighting the pivotal role of pediatric ID specialists, including the establishment and maintenance of antimicrobial stewardship programs, pediatric ID consultations and introduction of viral diagnosis by polymerase chain reaction at institutions. However, several issues need to be addressed, including the establishment of independent pediatric ID departments in institutions, payment of consultation fees, program site visits, maintenance of certification and cultivation of physician-scientists. These challenges will be the focus of future efforts., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Antimicrobial resistance is a global issue, and implementation of antimicrobial stewardship programs in outpatient settings is crucial. Japan has also focused on outpatient oral antimicrobial stewardship programs and difficulties in standardizing prescriptions have led to overprescription in primary emergency medical centers. There is a lack of research investigating the antibiotic prescription status of pediatric primary emergency medical centers and the benchmark prescription rates in pediatric outpatient settings., Methods: We conducted a multi-center, cross-sectional study of seven pediatric primary emergency medical centers located in five prefectures of Japan. We retrospectively extracted data from health claims or directly obtained them from charts at each institution and evaluated trends in the antibiotic prescription rate based on the AWaRe classification between April 2016 and December 2019., Results: Our study included 383,525 encounters, with the most common infectious disease diagnosis being acute upper respiratory tract infection in 93,449 cases (24.4 %). The antibiotic prescription rate during the study period was 7.4 %, representing a decrease of 46 %, from 10.2 % in 2016 to 5.5 % in 2019. The percentage of prescriptions in the Access group increased at all institutions; however, it exceeded 60 % in only three facilities in 2019. The percentage of third-generation cephalosporins varied among facilities, ranging from 1.7 % to 59.4 %, as of 2019., Conclusions: For pediatric primary emergency medical centers where antimicrobial stewardship programs are implemented, we suggest 5 % as a reasonable benchmark level for the antibiotic prescription rate. Prescribing the antibiotics in the Access groups less frequently remains a domestic challenge in Japan., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to disclose. Informed Consent and Ethical Approval. We obtained opt-out consent from the patients' parents. This study was approved by the institutional ethics committees of Kobe Children's Hospital (Approval Number 2021–61)., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: COVID-19 has become widespread in Japanese children. However, the impact of varying immunization coverage on the seroprevalence of SARS-CoV-2 in children is unknown., Methods: We examined the SARS-CoV-2 antibody in children aged 0 to 18 who were hospitalized at a university hospital from June 2020 through May 2023. The SARS-CoV-2 anti-nucleoprotein (N) antibody and anti-RBD spike (S) protein antibody was measured., Results: A total of 586 cases were enrolled. The median age was 4 years old (interquartile range 1-9), and 362 (61.8 %) were male. The seroprevalence of anti-S antibodies gradually increased from October 2021 and reached 60 percent by early 2023. The anti-N antibody increased starting in January 2022 and reached 50 percent in May 2023. There was a discrepancy in the seroprevalence of anti-S and N antibodies in children 0 years of age or 12 years and older until the fall of 2022. This discrepancy was minimal for children 1-4 years of age and relatively small in the 5-11-year-old group., Discussion: The data suggests that approximately half of the children in our cohort had been infected with SARS-CoV-2 by May 2023. The discrepancy in seropositivity between the anti-S and N antibodies corresponded to the reported vaccine uptake of each target age group, which suggested protective effects of immunization. However, this effect appeared to diminish after early 2023., Conclusion: Age dependent discrepancy between SARS-CoV-2 anti-N and anti-S antibody in children reflected differences in vaccine coverage., Competing Interests: Declaration of competing interest IM has received honoraria for lectures from; Pfizer, AstraZeneca, Shionogi, Meiji Seika Pharma, Daiichi-sankyo, Biken, Takeda pharmaceuticals, and Sanofi. The other authors have no conflict of interest to declare., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: The melting temperature (T m ) mapping method (TM) identifies bacterial species by intrinsic patterns of T m values in the 16S ribosomal RNA gene (16S rDNA) extracted directly from whole blood. We examined potential clinical application of TM in children with bloodstream infection (BSI)., Methods: This was a prospective observational study at a children's hospital in Japan from 2018 to 2021. In patients with diagnosed or suspected BSI, we investigated the match rates of pathogenic bacteria identified by TM and blood culture (BC), the inspection time to identification of TM, and the amount of bacterial DNA in blood samples., Results: The median age of 81 patients (93 samples) was 3.6 years. Of 23 samples identified by TM, 11 samples matched the bacterial species with BC (positive-match rate, 48 %). Of 64 TM-negative samples, 62 samples were negative for BC (negative-match rate, 97 %). Six samples, including one containing two pathogenic bacterial species, were not suitable for TM identification. In total, the matched samples were 73 of 93 samples (match rate, 78 %). There were seven samples identified by TM in BC-negative samples from blood collected after antibiotic therapy. Interestingly, the bacteria were matched with BC before antibiotic administration. These TM samples contained as many 16S rDNA copies as the BC-positive samples. The median inspection time to identification using TM was 4.7 h., Conclusions: In children with BSI, TM had high negative-match rates with BC, the potential to identify the pathogenic bacteria even in patients on antibiotic therapy, and more rapid identification compared to BC., Registering Clinical Trials: UMIN000041359https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000047220., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The coronavirus disease-2019 (COVID-19) pandemic presented an unprecedented challenge to societies, necessitating adaptations in infection prevention measures. While there is ample data on infection prevention practices in workplace and healthcare settings, comprehensive data specific to childcare facilities has been lacking., Methods: We conducted a nationwide web-based survey capturing responses from various childcare facilities (N = 549). This aimed to understand the adaptation in infection prevention measures between fiscal years 2022 and 2023, the status of events and activities, and the factors influencing decision-making related to infection prevention., Results: From 2022 to 2023, most childcare facilities reduced infection prevention practices like mandatory mask-wearing (46.9 %-7.5 %) and eating without conversing (56.5 %-7.4 %), whereas they continued high levels of hand sanitization and checking child's health condition before attendance. The frequency of events and activities (e.g., athletic meets, field trips) increased, with many being held without restrictions. Surprisingly, 62.8 % of facilities used items not recommended for infection prevention. The influence of local government guidelines (risk ratio, 0.69; 95%CI, 0.53-0.90) and the input from junior teachers (risk ratio, 0.85; 95%CI, 0.72-0.99) were associated with reduced risk of using inappropriate items. Furthermore, childcare facilities emphasized the need to collaborate with public health and medical professionals for more accurate and efficient decision-making during pandemics., Conclusions: The survey provides insights into the evolving practices of Japanese childcare facilities during the COVID-19 pandemic. It underscores the importance of refining information sources, enhancing decision-making processes, and fostering collaboration with the medical community for future pandemics and natural disasters., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Airway obstruction caused by viscous mucus is an important pathophysiologic characteristic of persistent inflammation, which can result in organ damage., Objective: We investigated the hypothesis that the biophysical characteristics of accumulating granulocytes affect the clinical properties of mucus., Methods: Surgically acquired nasal mucus samples from patients with eosinophilic chronic rhinosinusitis and neutrophil-dominant, noneosinophilic chronic rhinosinusitis were evaluated in terms of computed tomography density, viscosity, water content, wettability, and protein composition. Isolated human eosinophils and neutrophils were stimulated to induce the formation of extracellular traps, followed by the formation of aggregates. The biophysical properties of the aggregated cells were also examined., Results: Mucus from patients with eosinophilic chronic rhinosinusitis had significantly higher computed tomography density, viscosity, dry weight, and hydrophobicity compared to mucus from patients with noneosinophilic chronic rhinosinusitis. The levels of eosinophil-specific proteins in mucus correlated with its physical properties. Eosinophil and neutrophil aggregates showed physical and pathologic characteristics resembling those of mucus. Cotreatment with deoxyribonuclease and heparin, which slenderizes the structure of eosinophil extracellular traps, efficiently induced reductions in the viscosity and hydrophobicity of both eosinophil aggregates and eosinophilic mucus., Conclusions: The present study elucidated the pathogenesis of mucus stasis in infiltrated granulocyte aggregates from a novel perspective. These findings may contribute to the development of treatment strategies for eosinophilic airway diseases., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents., Methods: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6-15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires., Results: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year., Conclusions: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Long tubular duplication is a rare congenital intestinal disease, that can lead to emergency situations marked by massive hemorrhage. However, preoperative diagnosis and surgical treatment are challenging. This report presents preoperative images and details a surgical procedure for long tubular intestinal duplications with massive hemorrhage., Case Presentation: A 3-year-old boy presented to the emergency department with melena. Despite undergoing a Tc-99m pertechnetate scintigraphy one year prior, which revealed nonspecific findings with enhancement of some parts of the intestine, enhanced abdominal CT revealed an edematous small intestine with luminal extravasation. The patient received a transfusion of red blood cells; however, his hemoglobin level did not improve. Arterial angiography and double-balloon endoscopy revealed no remarkable findings. Exploratory laparotomy revealed a long tubular duplication in half of the small intestine. Utilizing the Wrenn procedure, we successfully removed all duplicate mucosa. Pathological findings showed that almost all duplications contained gastric mucosa and revealed an ulcer with a ruptured arterial vessel. His symptoms were resolved, and the hemoglobin level stabilized. At 2 months postoperatively, no surgical complications were present., Conclusions: Effective management of long tubular duplications with massive hemorrhage involves timely application of the Wrenn procedure. Recognition of specific imaging findings is crucial to prompt exploratory laparotomy, ensuring optimal outcomes and preventing delays in treatment., (© 2024. The Author(s).)

There are few reports on the association between antipyretic use and antibody titers in adolescents and young adults following SARS-CoV-2 vaccination. Multivariable linear regression analyses were performed to examine the association between antipyretic use and antibody titers. The use of antipyretics was not associated with antibody titers (β coefficient [95% CI] = -0.107 [-0.438 to 0.224])., Competing Interests: Declaration of competing interest KS received honoraria from Viatris Inc. All other coauthors do not have any conflicts of interests to disclose directly related to the study., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Exanthems are a common reason for visits to the pediatric emergency department. However, epidemiological data in the post-measles-rubella vaccine era is limited., Objective: We sought to determine the recent causes of exanthems in children younger than 6 years old in the pediatric emergency department., Methods: A prospective single-center study was conducted in Japan from August 2019 to March 2020. Children younger than 6 years old with exanthems were enrolled. Exanthems were classified into 7 morphological patterns. Varicella, herpes zoster, impetigo, urticaria and Kawasaki disease were diagnosed clinically. Nasopharyngeal swab specimens were collected from patients with nonspecific exanthems and evaluated by polymerase chain reaction (PCR) assays capable of detecting 24 pathogens. The final diagnosis was made by discussion of 3 physicians based on clinical course and microbiology., Results: There were 9705 pediatric visits, of which 296 (3%) had exanthems and were younger than 6 years old. Clinical diagnosis was possible for 160 (54%), including urticaria in 110 (37%), Kawasaki disease in 29 (10%), impetigo in 10 (3%), varicella or herpes zoster in 7 (2%) and group A Streptococcus in 4 (1%). Among the remaining 136 (46%) children, 75 (25%) underwent testing by PCR. One or more pathogens were detected in 49 (65%), specifically enterovirus in 14 (19%), cytomegalovirus in 13 (17%), human herpesvirus type-6 in 12 (16%), adenovirus in 11 (15%) and human herpesvirus type-7 in 8 (11%). Final infectious disease diagnoses were roseola infantum in 11 (15%), enterovirus in 9 (12%), adenovirus in 6 (8%), mixed virus infection in 5 (7%), group A Streptococcus in 3 (4%), parechovirus-A in 3 (4%) and influenza in 3 (4%)., Conclusions: The most common causes of pediatric exanthems were noninfectious diseases and viral exanthema. PCR assay was instrumental for etiological diagnosis of nonspecific exanthems., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

More than half of cases with suspected genetic disorders remain unsolved by genetic analysis using short-read sequencing such as exome sequencing (ES) and genome sequencing (GS). RNA sequencing (RNA-seq) and long-read sequencing (LRS) are useful for interpretation of candidate variants and detection of structural variants containing repeat sequences, respectively. Recently, adaptive sampling on nanopore sequencers enables target LRS more easily. Here, we present a Japanese girl with premature chromatid separation (PCS)/mosaic variegated aneuploidy (MVA) syndrome. ES detected a known pathogenic maternal heterozygous variant (c.1402-5A>G) in intron 10 of BUB1B (NM&#95;001211.6), a known responsive gene for PCS/MVA syndrome with autosomal recessive inheritance. Minigene splicing assay revealed that almost all transcripts from the c.1402-5G allele have mis-splicing with 4-bp insertion. GS could not detect another pathogenic variant, while RNA-seq revealed abnormal reads in intron 2. To extensively explore variants in intron 2, we performed adaptive sampling and identified a paternal 3.0 kb insertion. Consensus sequence of 16 reads spanning the insertion showed that the insertion consists of Alu and SVA elements. Realignment of RNA-seq reads to the new reference sequence containing the insertion revealed that 16 reads have 5' splice site within the insertion and 3' splice site at exon 3, demonstrating causal relationship between the insertion and aberrant splicing. In addition, immunoblotting showed severely diminished BUB1B protein level in patient derived cells. These data suggest that detection of transcriptomic abnormalities by RNA-seq can be a clue for identifying pathogenic variants, and determination of insert sequences is one of merits of LRS., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: The trends in clinical practice patterns and health resource use, as well as risk factors for severe conditions among children hospitalized with coronavirus disease-2019 (COVID-19), remain unclear., Materials and Methods: We conducted a retrospective observational study consisting of 9876 children hospitalized with COVID-19 during 2020-2022 using the Medical Data Vision database in Japan. We investigated trends in patient characteristics, health resource use, treatment patterns and laboratory data. Additionally, log-binomial regression models were used to investigate the risk factors associated with severe COVID-19 among pediatric inpatients with COVID-19., Results: We observed decreasing trends in the lengths of hospital stays, healthcare costs, computed tomography use, and antibiotic use, and increasing trends in treatment with intravenous hydration and use of antipyretics, antiepileptics, antiemetics and antivirals from the first wave to the seventh wave of COVID-19 pandemic. During the 3-year period, the risk of severe COVID-19 was almost stable at 3%. Risk factors associated with severe COVID-19 were children less than 1 year old [risk ratio (RR): 1.69; 95% confidence interval (CI): 1.02-2.78], the number of complex chronic diseases (RR for 1 disease: 4.49; 95% CI: 2.76-7.32; RR for 2 or more diseases: 10.2; 95% CI: 5.19-20.3) and asthma (RR: 1.84; 95% CI: 1.06-3.20)., Conclusions: Our study observed the changes in practice patterns and health resource use for children hospitalized with COVID-19 and identified risk factors associated with severe COVID-19. These findings indicate the importance of vigilant monitoring and tailored treatment strategies in children with these risk factors., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The nationwide epidemiology and clinical practice patterns for younger children hospitalized with urinary tract infections (UTIs) were unclear., Methods: We conducted a retrospective observational study consisting of 32,653 children aged < 36 months who were hospitalized with UTIs from 856 medical facilities during fiscal years 2011-2018 using a nationally representative inpatient database in Japan. We investigated the epidemiology of UTIs and changes in clinical practice patterns (e.g., antibiotic use) over 8 years. A machine learning algorithm of multivariate time-series clustering with dynamic time warping was used to classify the hospitals based on antibiotic use for UTIs., Results: We observed marked male predominance among children aged < 6 months, slight female predominance among children aged > 12 months, and summer seasonality among children hospitalized with UTIs. Most physicians selected intravenous second- or third-generation cephalosporins as the empiric therapy for treating UTIs, which was switched to oral antibiotics during hospitalizations for 80% of inpatients. Whereas total antibiotic use was constant over the 8 years, broad-spectrum antibiotic use decreased gradually from 5.4 in 2011 to 2.5 days of therapy per 100 patient-days in 2018. The time-series clustering distinctively classified 5 clusters of hospitals based on antibiotic use patterns and identified hospital clusters that preferred to use broad-spectrum antibiotics (e.g., antipseudomonal penicillin and carbapenem)., Conclusions: Our study provided novel insight into the epidemiology and practice patterns for pediatric UTIs. Time-series clustering can be useful to identify the hospitals with aberrant practice patterns to further promote antimicrobial stewardship. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The members of the Japanese Society for Pediatric Infectious Diseases and the Japanese Society of Pediatric Pulmonology have developed Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating appropriate diagnosis, treatment and prevention of respiratory infections in children. The first edition was published in 2004 and the fifth edition was published in 2022. The Guideline 2022 consists of 2 parts, clinical questions and commentary, and includes general respiratory infections and specific infections in children with underlying diseases and severe infections. This executive summary outlines the clinical questions in the Guidelines 2022, with reference to the Japanese Medical Information Distribution Service Manual. All recommendations are supported by a systematic search for relevant evidence and are followed by the strength of the recommendation and the quality of the evidence statements., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical efficacy of remdesivir in children with COVID-19 is unclear. This propensity-score-matched retrospective cohort study of children with COVID-19 showed that the rate of patients achieving defervescence on Day 4 was higher in the remdesivir group than in the non-remdesivir group, but was not statistically different (86.7% vs 73.3%, P = 0.333)., Competing Interests: Declaration of competing interest K. Shoji received payment for lectures from bioMérieux Japan, Nippon Becton Dickinson Company, Ltd., Viatris, Inc., Meiji Seika Pharma Co., Ltd., AstraZeneca K.K., Novartis Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Gilead Sciences, Inc. S. Tsuzuki received payment for supervising medical articles from Gilead Sciences, Inc. I. Miyairi received payment for lectures from Astellas Pharma, Sanofi K.K., Pfizer, Inc., Takeda Pharmaceutical Company, Ltd., Biken Group, Shionogi & Company, Ltd., bioMérieux Japan, and Gilead Sciences, Inc. The other authors declare that they do not have any conflicts of interests directly associated with the study., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

The development of antibiotics that are acceptable and easy for children to take and use is highly desirable. As advocated by the World Health Organization, solid oral formulations with excellent shelf-life, taste masking and dose adjustment are attracting attention as appropriate pediatric oral antimicrobial formulations, but liquid formulations remain the most common worldwide. Apparently unique to Japan, the most common formulations of oral antimicrobials for pediatric use are dispensed as a powder with most being flavored powders. Powdered formulations are packaged in single doses, which eliminates the need for parents to weigh them before administration and may reduce the possibility of dosage errors. On the other hand, there are some formulations that require large doses of powder due to inappropriate concentrations, granular formulations that have a rough texture that affects palatability, and some formulations that require flavoring agents to mask the bitter taste of the main drug. Such inappropriate formulations have a significant impact on adherence to antimicrobial therapy. It remains unclear whether solid oral dosage forms might be as acceptable worldwide as in Japan. To ensure that appropriate antimicrobials are delivered to children worldwide, a direction for the development of appropriate dosage forms in children needs to be established., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To determine the epidemiological trends in pediatric influenza and changes in healthcare resource use from 2005 to 2021 using nationally representative outpatient database in Japan., Methods: We conducted a retrospective cohort study consisting of 3.5 million children with 177 million person-months during 2005-2021 using Japan Medical Data Center claims database in Japan. We investigated trends in incidence rates of influenza and changes in healthcare resource use (eg, use of antivirals) over 17 years. Generalized estimation equations were used to investigate the impact of the 2009 influenza pandemic and the coronaviral disease 2019 (COVID-19) pandemic on incidence rates of influenza and related healthcare utilization., Results: Annual incidence rates of influenza were estimated at 55 cases per 1000 person-years with a 93% relative increase [95% confidence interval (CI): 80%-107%] during the 2009 influenza pandemic and a 99.4% relative reduction (95% CI: 99.3%-99.4%) during the COVID-19 pandemic. Similar patterns were observed for health resource use, total healthcare costs, admission rates and antiviral agent use. Approximately 80% of children with influenza received prescriptions for antivirals. The most prescribed antivirals were oseltamivir, but we observed a temporal increase in zanamivir use during 2007-2009, an increasing trend in laminamivir use during 2010-2017, a temporal increase in baloxavir use in 2018. Symptomatic medications with serious side effects (codeine, salicylate, sedative antihistamine) showed decreasing trends over the study period., Conclusions: Influenza incidence and healthcare resource use were largely affected by the 2009 influenza pandemic and the COVID-19 pandemic. Our study indicates improvement of quality in healthcare delivered to children., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To determine the epidemiological trends in pediatric varicella and herpes zoster incidence and changes in healthcare resource use from 2005 to 2022 using a nationally representative database in Japan., Materials and Methods: We conducted a retrospective observational study consisting of 3.5 million children with 177 million person-months during 2005-2022 using Japan Medical Data Center (JMDC) claims database in Japan. We investigated trends in incidence rates of varicella and herpes zoster and changes in healthcare resource use (e.g., antiviral use, office visits, and healthcare costs) over 18 years. Interrupted time-series analyses were used to investigate the impact of the routine varicella vaccination program in 2014 and infection prevention measures against COVID-19 on incidence rates of varicella and herpes zoster and related healthcare utilization., Results: After the introduction of the routine immunization program in 2014, we observed level changes in incidence rates (45.6 % reduction [95 %CI, 32.9-56.0] of varicella cases, antiviral use (40.9 % reduction [95 %CI, 25.1-53.3]), and relevant healthcare costs (48.7 % reduction [95 %CI, 38.2-57.3]). Furthermore, infection prevention measures against COVID-19 were associated with additional level changes in varicella rates (57.2 % reduction [95 %CI, 44.5-67.1]), antiviral use (65.7 % reduction [59.7-70.8]), and healthcare costs (49.1 % [95 %CI, 32.7-61.6]). In contrast, the changes in incidence and healthcare costs for herpes zoster were relatively small, which showed 9.4 % elevated level change with a decreasing trend and 8.7 % reduced level change with a decreasing trend after the vaccine program and the COVID-19 pandemic. The cumulative incidence of herpes zoster in children born after 2014 was lower than that before 2014., Conclusions: Varicella incidence and healthcare resource use were largely affected by the routine immunization program and infection prevention measures against COVID-19, while these impacts on herpes zoster were relatively small. Our study indicates that immunization and infection prevention measures largely changed pediatric infectious disease practices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Several reports have suggested that routine use of anaerobic blood culture bottles together with aerobic bottles may improve blood culture positivity. However, the information is still limited regarding the utility of anaerobic blood culture bottles in the pediatric intensive care unit (PICU), where bacteremia due to anaerobic bacteria is relatively rare., Methods: A retrospective observational study was conducted at a PICU in a tertiary children's hospital in Japan from May 2016 to January 2020. Patients aged ≤15 years old with bacteremia, for which both aerobic and anaerobic blood cultures were submitted, were included in the study. We investigated whether the positive blood culture cases were from aerobic or anaerobic bottles. We also compared the amount of blood inoculated into culture bottles to determine the effect of blood volume on the rate of detection., Results: During the study period, a total of 276 positive blood cultures from 67 patients were included in this study. Among the paired blood culture bottles, 22.1% were positive only for the anaerobic bottles. Escherichia coli and Enterobacter cloacae were the most common pathogens that were detected in anaerobic bottles only. Obligate anaerobic bacteria were detected in 2 (0.7%) bottles. There was no significant difference in the amount of blood inoculated into aerobic and anaerobic culture bottles., Conclusions: The use of anaerobic blood culture bottles in the PICU may increase the detection rate of facultative anaerobic bacteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (STEC-HUS). Understanding its prognostic factors is essential for immediate interventions. We examined early-phase unfavorable prognostic factors among patients with STEC-HUS using a nationwide database., Material and Methods: This is a retrospective cohort study to analyze practice patterns and identify prognostic factors among patients with STEC-HUS. We used the Diagnosis Procedure Combination Database, which includes approximately half of the acute-care hospitalized patients in Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. The composite unfavorable outcome included in-hospital death, mechanical ventilation, dialysis, and rehabilitation at discharge. Unfavorable prognostic factors were assessed using a multivariable logistic regression model., Results: We included 615 patients with STEC-HUS (median age, 7 years). Of them, 30 (4.9%) patients had acute encephalopathy and 24 (3.9%) died within 3 months of admission. Unfavorable composite outcome was observed in 124 (20.2%) patients. Significant unfavorable prognostic factors were age of 18 years or older, methylprednisolone pulse therapy, antiepileptic drug administration, and respiratory support within 2 days of admission., Discussion: Patients requiring early steroid pulse therapy, antiepileptic drugs, and respiratory support were considered to be in poor general condition; such patients should receive aggressive intervention to avoid worse outcomes., Competing Interests: Conflicts of interest All authors declare that they do not have any conflicts of interests directly associated with the study., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan., Methods: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021., Results: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%)., Conclusions: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Data are limited regarding the safety of and antibody response to the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid vaccine in adolescents and young adults with underlying disease., Methods: This prospective observational study enrolled patients age 12-25 years with chronic underlying disease who received 2 doses of BNT162b2. A 18-item questionnaire was used to assess adverse events within 7 days post-vaccination, and data regarding severe adverse events were collected from electronic medical records. An antibody titer for the receptor-binding domain of the spike protein in SARS-CoV-2 was used to assess antibody response after the second vaccine dose., Results: Study participants were 429 patients (241 [56.2%] age 12-15 years; 188 [43.8%] age 16-25 years). The most common underlying diseases were genetic or chromosomal abnormalities and/or congenital anomalies, followed by endocrine or metabolic diseases; 32% of participants were immunocompromised. Severe adverse events were observed after the second dose in 1 (0.4%) patient age 12-15 years and in 2 (1.1%) patients age 16-25 years; all patients recovered. Seropositivity after the second vaccine dose was 99.0%. The geometric mean antibody titer was higher in patients age 12-15 years versus 16-25 years (1603.3 [1321.8-1944.7] U/mL vs. 949.4 [744.2-1211.0] U/mL). Compared with immunocompetent patients, immunocompromised patients had a lower antibody titer (2106.8 [1917.5-2314.7] U/mL vs. 467.9 [324.4-674.8] U/mL)., Conclusions: Vaccination with BNT162b2 was acceptably safe and immunogenic for adolescents and young adults with underlying disease., Competing Interests: Declaration of competing interest K. Shoji received payment for lectures from Biomelieux Japan, Gilead and VIATRIS. All the other authors have indicated they have no conflict of interests directly associated with this work., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Information regarding effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant strains on clinical manifestations and outcomes of coronavirus disease 2019 (COVID-19) in pregnant women is limited., Methods: A retrospective observational study was conducted using the data from the nationwide COVID-19 registry in Japan. We identified pregnant patients with symptomatic COVID-19 hospitalized during the study period. The Delta and Omicron variants of concern (VOC) predominant periods were defined as August 1 to December 31, 2021 and January 1 to May 31, 2022, respectively. Clinical characteristics were compared between the patients in the Delta and Omicron VOC periods. In addition, logistic regression analysis was performed to identify risk factors for developing moderate-to-severe COVID-19., Results: During the study period, 310 symptomatic COVID-19 cases of pregnant women were identified; 111 and 199 patients were hospitalized during the Delta and Omicron VOC periods, respectively. Runny nose and sore throat were more common, and fatigue, dysgeusia, and olfactory dysfunction were less common manifestations observed in the Omicron VOC period. In the multivariable logistic regression analysis, onset during the later stage of pregnancy (OR: 2.08 [1.24-3.71]) and onset during the Delta VOC period (OR: 2.25 [1.08-4.90]) were independently associated with moderate-to-severe COVID-19, whereas two doses of SARS-CoV-2 vaccine were protective against developing moderate-to-severe COVID-19 (OR: 0.34 [0.13-0.84])., Conclusions: Clinical manifestations of COVID-19 in pregnant women differed between the Delta and Omicron VOC periods. SARS-CoV-2 vaccination was still effective in preventing severe COVID-19 throughout the Delta and Omicron VOC periods., Competing Interests: Declaration of competing interest K. Shoji received payment for lectures from Mitsubishi Tanabe Pharma, Astellas, AbbVie GK, Biomerieux Japan, Nippon Becton Dickinson Company, Ltd., VIATRIS and Gilead. S. Tsuzuki received payment for supervising medical articles from Gilead Sciences, Inc. The other authors declare that they do not have any conflicts of interests directly associated with the study., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Infectious diseases after transplantation account for significant morbidity and mortality in children undergoing transplantation; the importance of pediatric transplant infectious disease (TID) specialists has therefore been recognized. Although tremendous advancement continues in transplantation medicine, pediatric-specific data and evidence are limited. In Japan, the majority of TIDs had not been managed by infectious disease specialists because pediatric infectious diseases have not been recognized as a solo subspecialty until recently in Japan. However, in the last decade, there was a new movement for pediatric TID in Japan; some pediatric infectious disease specialists trained outside Japan have been playing an important role in managing pediatric TID in a few academic and pediatric institutions. In this review article, we introduce the current status of infectious complications related to pediatric hematopoietic cell and solid organ transplantation, highlighting currently available local evidence, common practice and issues in the field of pediatric TID in Japan., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: For addressing antibiotic overuse, Japan designed a health care policy in which eligible medical facilities could claim a financial reward when antibiotics were not prescribed for early-stage respiratory and gastrointestinal infections. The policy was introduced in a pilot manner in paediatric clinics in April 2018., Methods: We conducted a quasi-experimental, propensity score-matched, difference-in-differences (DID) design to determine whether the nationwide financial incentives for appropriate non-prescribing of antibiotics as antimicrobial stewardship [800 JPY (≈7.3 US D) per case] were associated with changes in prescription patterns, including antibiotics, and health care use in routine paediatric health care settings at a national level. Data consisted of 9 253 261 cases of infectious diseases in 553 138 patients treated at 10 180 eligible or ineligible facilities., Results: A total of 2959 eligible facilities claimed 316 770 cases for financial incentives and earned 253 million JPY (≈2.29 million USD). Compared with ineligible facilities, the introduction of financial incentives in the eligible facilities was associated with an excess reduction in antibiotic prescriptions [DID estimate, -228.6 days of therapy (DOTs) per 1000 cases (95% CI, -272.4 to -184.9), which corresponded to a relative reduction of 17.8% (95% CI, 14.8 to 20.7)]. The introduction was also associated with excess reductions in drugs for respiratory symptoms [DID estimates, -256.9 DOTs per 1000 cases (95% CI, -379.3 to -134.5)] and antihistamines [DID estimate, -198.5 DOTs per 1000 cases (95% CI, -282.1 to -114.9)]. There was no excess in out-of-hour visits [DID estimate, -4.43 events per 1000 cases (95% CI, -12.8 to 3.97)] or hospitalizations [DID estimate, -0.08 events per 1000 cases (95% CI, -0.48 to 0.31)]., Conclusions: Our findings suggest that financial incentives to medical facilities for not prescribing antibiotics were associated with reductions in prescriptions for antibiotics without adverse health care consequences. Japan's new health policy provided us with policy options for immediately reducing inappropriate antibiotic prescriptions by relatively small financial incentives., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis., Competing Interests: K.S. received payment for lectures from Mitsubishi Tanabe Pharma, Astellas, AbbVie GK, and G.H.N. received grants from the Japan Agency for Medical Research and Development, consulting fees from Taisho Pharmaceutical Co., Ltd., Sato Pharmaceutical Co., Ltd., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Eli Lilly Japan K.K. and Astra Zeneca K.K., and payment for lectures from Shionogi & Co., Ltd. and Chugai Pharmaceutical Co., Ltd. K.M. received grant support from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd. and payment for lectures from Meiji Seika Pharma Co., Ltd. Y.T. received grant support from Shionogi & Co., Ltd. and payment for lectures from Astellas Pharma Inc. and MSD Japan. I.M. received payment for lectures and consultations from Sanofi, Takeda Pharmaceuticals, Astellas Pharma Inc., Janssen Pharmaceuticals, Fujifilm Toyama Chemical Co., Biomelieux Japan, Abbott Japan Co. and AbbVie GK. The other authors have have no conflicts of interest to disclose. This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no. 21K16332)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Several studies have investigated whether pregnancy is a risk factor for developing severe coronavirus disease 2019 (COVID-19); however, the results remain controversial. In addition, the information regarding risk factors for developing severe COVID-19 in pregnant women is limited., Methods: A retrospective cohort study analyzing the data from the nationwide COVID-19 registry in Japan was conducted. Propensity score-matched analysis was performed to compare COVID-19 severity between pregnant and nonpregnant women. Multivariate analysis was also conducted to evaluate risk factors for developing moderate-to-severe COVID-19 in pregnant women., Results: During the study period, 254 pregnant and 3752 nonpregnant women of reproductive age were identified. After propensity score matching, 187 pregnant women and 935 nonpregnant women were selected. A composite outcome of moderate-to-severe COVID-19 was more frequently observed in pregnant women than that of nonpregnant women (n = 18 [9.6%] vs n = 46 [4.9%]; P = .0155). In multivariate analysis, the presence of underlying diseases and being in the second-to-third trimester of pregnancy were recognized as risk factors for moderate-to-severe COVID-19 in pregnant women (odds ratio [95% confidence interval]: 5.295 [1.21-23.069] and 3.871 [1.201-12.477], respectively)., Conclusions: Pregnancy could be a risk factor for moderate-to-severe COVID-19 for women in Japan. In addition to the presence of comorbidities, advanced pregnancy stages may contribute to greater risks for developing moderate-to-severe COVID-19 in pregnant women., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Antimicrobial resistance (AMR) is a threat to patient health. However, data to optimize antimicrobial use are limited. Furthermore, reducing antibiotic use raises concerns regarding patient safety. The effectiveness of antibiotics in reducing the prevalence of AMR is controversial. Researchers at the Japanese Red Cross Ishinomaki Hospital (JRCIH), the only tertiary care hospital in the medical zone, along with local medical and pharmacy associations and public health centers have been leading the AMR control program since 2018. The program involves lectures aimed at optimizing antimicrobial use, regular publication of surveillance data of drug-resistant strains at the JRCIH, and presentation of first-line treatments for community-acquired infections. The delivery of oral antimicrobial agents across the region in 2020 was 28.7% lower than that in 2013, with delivery of cephalosporins, quinolones, and macrolides decreasing by 34.8%, 46.8%, and 56.0%, respectively. Despite these reductions, there has been no associated increase in the number of patients with severe infectious diseases admitted to the JRCIH. The rates of representative drug-resistant bacterial strains, such as extended-spectrum beta-lactamase-producing Escherichia coli and methicillin-resistant Staphylococcus aureus, decreased by half. Herein, we demonstrated the potential of collaborative efforts to optimize antimicrobial agent use and reduce the AMR prevalence without compromising patient safety.

We describe a domestic case of retropharyngeal abscess (RPA) in a child caused by a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate that was genetically proven to be the USA300 clone (sequence type [ST]8-SCCmec IVa-Panton-Valentine leukocidin [PVL]). USA300 generally has a PVL gene, an epidemiologic association with severe and recurrent skin and soft tissue infection, and is the leading cause of RPA in the United States. A 1-year-old previously healthy girl visited the emergency department with fever, sore throat, and a difficulty in moving her neck. The patient had no recent medical exposure or history of travel abroad. Enhanced computed tomography revealed a bulky low-density area with ring enhancement in the retropharyngeal and right parapharyngeal spaces. MRSA was isolated from pus obtained from surgical drainage, and antibiotics were continued for a total of 21 days. MRSA was analyzed by whole genome sequencing and compared with representative USA300 isolates. The strain was typed as ST8-t9829-SCCmec IVa with PVL and arginine catabolic mobile element, and its sequence was 99.8% identical to USA300 isolates. The present case supports the possibility that USA300 is potentially spreading in the Japanese community and raises the possibility of USA300 invasive infections without a clear route of infection.