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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.)

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.)

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.)

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.)

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.)

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.)

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.)

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: The overutilization of healthcare and overuse/misuse of antibiotics in Japan are responsible for the increase in healthcare expenditure and the development of antimicrobial resistance. The Japanese government started paying incentives to medical facilities for primary care physician registrations, but the impact of this new policy is still unclear., Methods: We conducted a retrospective cohort study for all pediatric outpatients from April 2015 to December 2016 in Japan, targeting 1.4 million children under 2 years of age. We investigated the effects of primary care physician registration on physician visits, total antibiotic use and admission rates using difference-in-differences (DID) and causal mediation analyses., Results: DID analyses showed that primary care registration policy contributed to increases in total physician visits, total and broad-spectrum antibiotic use and radiologic study utilization, but reduced out-of-hour visits and did not affect hospitalization rates. Similar results were obtained when we adjusted for and matched on potential confounders. Causal mediation analyses found that the greatest pathway was controlled by direct effects of 53.2 DOTs per 1000 person-months (95% CI: 29.1-77.2), indicating that the effect of new health policy that did not mediate increased outpatient visits mostly contributed to the excess use of antibiotics., Conclusions: The health policy further increased antibiotic use. On April 2018, a new health policy of paying incentives for not prescribing antibiotics to children with respiratory infection or gastroenteritis was initiated. Further studies are needed whether this new health policy can mitigate the overutilization of healthcare and antibiotic use.

We encountered a case of Bacillus Calmette-Guérin (BCG) cervical lymphadenitis in a patient undergoing infliximab after 6 years from BCG vaccination. Tumor necrosis factor-α inhibitors may be a risk for reactivation of BCG and serious infection even several years after vaccination.

Background: Suppurative cervical lymphadenitis is rare in children with limited information about the frequency of neutropenia in any series., Methods: We conducted a retrospective review of pediatric patients in whom suppurative cervical lymphadenitis was diagnosed between April 2011 and March 2016 at a tertiary children's hospital in Tokyo, Japan. Microbiologically confirmed cases of cervical lymphadenitis with abscess formation were included in the analysis., Results: Twenty-five patients (median age, 1 yr old; 64% female) with abscess formation caused by Staphylococcus aureus were identified. Among these 25 patients, 5 (20%) met the criteria for chronic neutropenia and 4 (80%) received the final diagnosis of autoimmune neutropenia based on the identification of the serum anti-CD16 antibodies., Conclusions: Chronic neutropenia and autoimmune neutropenia were relatively common among infants with suppurative cervical lymphadenitis caused by S. aureus.

We identified 8 pediatric patients on micafungin (MCFG; ≥3 doses) at our institution who had breakthrough candidemia (BC). The causative strains of the BC were Candida parapsilosis in 7 patients. The minimum inhibitory concentration of MCFG was ≤1 µg/mL (susceptible) in all 8 isolates. Immunocompromised patients may develop BC caused by MCFG-susceptible strains.

Background: Enterococci can cause severe infectious diseases (IDs). Delaying appropriate antibiotic therapy for enterococcal bacteremia is associated with increased patient mortality., Methods: We conducted a retrospective analysis examining the characteristics of children with enterococcal bacteremia at the 2 largest children's hospitals in Japan. We compared outcomes of enterococcal bacteremia patients who received IDs consultation with those who did not. We also evaluated the risk factors for 30-day mortality after onset of enterococcal bacteremia., Results: One hundred fifty-two episodes of enterococcal bacteremia developed in 142 children. The most common pathogen was Enterococcus faecalis (94 episodes, 62%) followed by E. faecium (46 episodes, 30%). An underlying disease was present in 146 (96%) episodes. The most common type of infection was catheter-related blood stream infection (90, 59%). ID consultation, provided in 100 of 152 episodes of enterococcal bacteremia, was significantly associated with a higher rate of appropriate empiric therapy (84% versus 56%; P < 0.001) and appropriate definitive therapy (98% versus 73%; P < 0.001), treatment duration ≥7 days (97% versus 78%; P < 0.001), and the survival rate during 1 year postonset (P = 0.047). Seventeen children died within 30 days of enterococcal bacteremia onset. In multivariate analysis, those who received definitive therapy with penicillin without glycopeptides were at a statistically lower risk for death within 30 days after onset of enterococcal bacteremia (OR: 0.12; 95% confidence interval: 0.02-0.70; P = 0.02)., Conclusions: ID consultation was associated with a higher rate of appropriate therapy and may decrease mortality because of enterococcal bacteremia in children.

Background: Blood culture contamination (BCC) leads to unnecessary interventions including hospitalization, antibiotic administration and additional laboratory tests. Previous studies in adults revealed that BCC was associated with unnecessary financial expenditures. However, information pertaining to the pediatric population is limited. Therefore, we investigated the details of the adverse economic impact associated with BCC in a pediatric emergency department (ED) in Japan., Methods: This study was a retrospective, observational study. We collected data on blood cultures performed in patients 18 years of age in a pediatric ED. Medical records of patients with positive blood cultures were reviewed, and the information regarding adverse events related to BCC was extracted. Medical costs related to BCC were estimated from the data., Results: In total, 13,139 sets of blood cultures were performed from April 2013 to June 2016, and 141 cases (1.1%) of BCC were identified. Among these, 106 patients (75%) experienced at least 1 adverse event associated with BCC. The total medical cost due to BCC was 4,076,713 Japanese yen. Multifaceted approaches targeting ED physicians including lectures on optimal blood collection methods and monthly feedback on BCC rates were effective in reducing the BCC rate and its related costs., Conclusions: Interventions associated with BCC were common and accounted for significant adverse economic impact on pediatric patients. Regular education and monitoring were effective in reducing BCC and its related costs.

Background: Bloodstream infection (BSI) is a major cause of morbidity and mortality after pediatric liver transplantation (LT). However, most studies have focused on BSI occurring within a few months after LT. In this study, we evaluated the characteristics of BSI occurring beyond 6 months after pediatric LT., Methods: We conducted a retrospective cohort study at a pediatric LT center in Japan from November 2005 to March 2016. We evaluated the causative organisms and site of late-onset BSI in children ≤ 18 years of age. The risk factors for developing late-onset BSI and the associations of late-onset BSI with long-term outcomes were also evaluated., Results: Three hundred forty cases of LT were evaluated. Thirty-eight BSI developed in 29 (9%) LT recipients. There were 42 organisms (nine Gram-positive cocci, 33 Gram-negative rods) isolated from the blood cultures of recipients with late-onset BSI. The most frequent sites of late-onset BSI was intraabdominal infection (18/38; 47%). There were also 14 (39%) episodes with no apparent focus. In multivariate analysis, a prolonged operative time > 12 hours (odds ratio [OR] = 3.55; P = 0.04) and biliary stenosis (OR = 4.60; P = 0.006) were independent risk factors for developing late-onset BSI. Late-onset BSI was associated with increased retransplantation rate (P = 0.04) and mortality (P < 0.001)., Conclusion: Late-onset BSI developed in 9% of recipients after pediatric LT. Gram-negative rods accounted for the majority of late-onset BSI as a consequence of abdominal infection, but the focus was often unclear. Prolonged operative time at LT and biliary stenosis were independent risk factors for developing late-onset BSI.

Background: Postoperative bloodstream infection (BSI) is the most important determinant of recipient morbidity and mortality after liver transplantation (LT). Children who underwent LT are at the highest risk of developing BSI because of the significant surgical intervention, use of multiple devices, and administration of immunosuppressive agents. However, information regarding the risk factors for BSI in children after LT is limited., Methods: We retrospectively reviewed 210 children who underwent living-donor LT at the largest pediatric LT center in Japan. Patients' characteristics, blood culture results and clinical outcomes were extracted from electronic medical records. Univariate and multivariate analyses were performed to identify the risk factors for BSI., Results: Among the 210 LT recipients, 53 (25%) recipients experienced 86 episodes of BSI during the observational period. The source of the BSI was identified only in 38%: catheter-related BSI (27%) peritonitis (7%), urinary tract infection (2%), pneumonia (1%) and infectious endocarditis (1%). A multivariate analysis demonstrated that body weight (P = 0.03), volume of blood loss during LT (P < 0.001) and cytomegalovirus (CMV) antigenemia positivity (P = 0.04) were independently associated with the development of BSI. The risk factors for BSI differed when we analyzed the subjects according to age (≤24 months and >24 months), blood loss and pediatric end-stage liver disease/model for end-stage liver disease versus positive CMV antigenemia., Conclusions: The volume of blood loss, postoperative CMV antigenemia positivity and body weight were associated with the development of BSI after LT in pediatric living-donor recipients. To identify the age-specific predictors of BSI in children who underwent LT, age-specific analyses are crucial.

Background: Human parechovirus type 3 (HPeV3) infection can cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. Although maculopapular rash is a reported clinical manifestation of HPeV3 infection, the frequency and detailed characteristics of rash in neonates and young infants with HPeV3 infection are unknown., Methods: We retrospectively reviewed the clinical characteristics of neonates and young infants who received a diagnosis of HPeV3 infection on the basis of real-time polymerase chain reaction analysis of serum and/or cerebrospinal fluid specimens at the National Center for Child Health and Development in Tokyo between November 2010 and September 2011., Results: Fifteen neonates and young infants were diagnosed as having HPeV3 infection; median age was 33 days (range: 10-81 days). The most common clinical presentation on admission was fever (80%), the median duration of which was 3 days (range: 1-4 days). Five (33%) children required admission to the intensive care unit for close observation, and 2 (13%) required mechanical ventilation for cardiovascular instability. After hospitalization, all children developed rash, mainly on the extremities, at a mean of 3 days (range: 1-5 days) after fever onset. The most striking finding was that 80% (12/15) of patients developed a distinctive palmar-plantar erythematous rash, which disappeared after a median of 3 days (range: 2-7 days). All patients were discharged from hospital without serious sequelae., Conclusions: Palmar-plantar erythema in febrile neonates and young infants may be a diagnostic clue of HPeV3 infection.

An 8-year-old girl with leukemia developed acute necrotizing ulcerative gingivitis with Stenotrophomonas maltophilia and herpes simplex virus. Progression to bacteremia with pathologic evidence of osteomyelitis occurred despite appropriate antimicrobial therapy. This case highlights the importance of prompt recognition, debridement and appropriate therapy in immunocompromised patients with acute necrotizing ulcerative gingivitis.

We present a fatal case of neonatal invasive group A streptococcal disease and review of the literature. Twenty-four cases were early onset disease and were associated with concurrent maternal infection, respiratory distress, pneumonia, toxic shock-like syndrome and serotype M1. Fifteen cases were late onset disease associated with soft tissue infections and meningitis. Maternal carriage was identified as an important factor in neonatal group A streptococcal disease.