Launch of Board Certification in Pediatric Infectious Diseases in Japan.

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.

Severe Bronchopulmonary Dysplasia Adversely Affects Brain Growth in Preterm Infants.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is associated with neurodevelopmental outcomes of preterm infants, but its effect on brain growth in preterm infants after the neonatal period is unknown. This study aimed to evaluate the effect of severe BPD on brain growth of preterm infants from term to 18 months of corrected age (CA). METHODS: Sixty-three preterm infants (42 with severe BPD and 21 without severe BPD) who underwent magnetic resonance imaging at term equivalent age (TEA) and 18 months of CA were studied by using the Infant Brain Extraction and Analysis Toolbox (iBEAT). We measured segmented brain volumes and compared brain volume and brain growth velocity between the severe BPD group and the non-severe BPD group. RESULTS: There was no significant difference in brain volumes at TEA between the groups. However, the brain volumes of the total brain and cerebral white matter in the severe BPD group were significantly smaller than those in the non-severe BPD group at 18 months of CA. The brain growth velocities from TEA to 18 months of CA in the total brain, cerebral cortex, and cerebral white matter in the severe BPD group were lower than those in the non-severe BPD group. CONCLUSION: Brain growth in preterm infants with severe BPD from TEA age to 18 months of CA is less than that in preterm infants without severe BPD.

Successful oral midodrine therapy for treatment of refractory postoperative chylothorax in an infant.

Refractory chylothorax, a postoperative complication of CHD, is difficult to manage and sometimes fatal. Herein, we report the case of a 10-month-old infant with 22-mosaic trisomy and a coarctation complex, who developed refractory chylothorax after cardiac repairs and was successfully treated with midodrine, an oral alpha-1-adrenoreceptor agonist. Midodrine may be used as adjunctive therapy for postoperative refractory chylothorax.

Clinical and molecular analyses of isolated central congenital hypothyroidism based on a survey conducted in Japan.

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology. The known causes of isolated central CH were studied in 14 patients, including six with previously reported patient data. The results revealed IGSF1 and TBL1X pathogenic variants in nine and one patient, respectively. All six patients with low free thyroxine (FT4) levels detected in NBS carried IGSF1 pathogenic variants. Five patients with isolated central CH diagnosed after 3 months of age were variant-negative, except for one female patient with a heterozygous IGSF1 variant. Two of the four variant-negative patients and a variant-positive patient were diagnosed with pituitary hypoplasia. One and two patients with IGSF1 variant had obesity and intellectual disability, respectively. Left amblyopia was identified in the patient with a TBL1X variant. The study revalidated that IGSF1 variants comprise the most frequent pathogenic variant in patients with isolated central CH in Japan. The neonatal period is the optimal time for the diagnosis of central CH, particularly IGSF1 abnormalities, and the introduction of T4 screening should be considered in the future, taking cost-effectiveness into consideration.

Acute Flaccid Myelitis With Human Rhinovirus A19 Detection: Case Report and Literature Review.

Human rhinovirus (HRV) has been sporadically detected in patients with acute flaccid myelitis (AFM). We report a case of AFM in a 2-year-old boy with severe neurologic sequelae, whose nasopharyngeal and stool samples tested positive for HRV-A19. Clinical information related to AFM with HRV is limited. Further study of the association of AFM with HRV is warranted.

Over-investigation and overtreatment in pediatrics: a survey from the European Academy of Paediatrics and Japan Pediatric Society.

Introduction: Avoiding over-investigation and overtreatment in health care is a challenge for clinicians across the world, prompting the international Choosing Wisely campaign. Lists of recommendations regarding medical overactivity are helpful tools to guide clinicians and quality improvement initiatives. We aimed to identify the most frequent and important clinical challenges related to pediatric medical overactivity in Europe and Japan. Based on the results, we aim to establish a (European) list of Choosing Wisely recommendations. Methods: In an online survey, clinicians responsible for child health care in Europe and Japan were invited to rate 18 predefined examples of medical overactivity. This list was compiled by a specific strategic advisory group belonging to the European Academy of Paediatrics (EAP). Participants were asked to rate on a Likert scale (5 as the most frequent/important) according to how frequent these examples were in their working environment, and how important they were considered for change in practice. Results: Of 2,716 physicians who completed the survey, 93% (n = 2,524) came from 17 countries, Japan (n = 549) being the largest contributor. Pediatricians or pediatric residents comprised 89%, and 51% had 10-30 years of clinical experience. Cough and cold medicines, and inhaled drugs in bronchiolitis were ranked as the most frequent (3.18 and 3.07 on the Likert scale, respectively), followed by intravenous antibiotics for a predefined duration (3.01), antibiotics in uncomplicated acute otitis media (2.96) and in well-appearing newborns. Regarding importance, the above-mentioned five topics in addition to two other examples of antibiotic overtreatment were among the top 10. Also, IgE tests for food allergies without relevant medical history and acid blockers for infant GER were ranked high. Conclusion: Overtreatment with antibiotics together with cough/cold medicines and inhaled drugs in bronchiolitis were rated as the most frequent and important examples of overtreatment across countries in Europe and Japan.

Detection of enterovirus D68 among children with severe acute respiratory infection in Myanmar.

BACKGROUND: Enterovirus D68 (EV-D68) is an important reemerging pathogen that causes severe acute respiratory infection and acute flaccid paralysis, mainly in children. Since 2014, EV-D68 outbreaks have been reported in the United States, Europe, and east Asia; however, no outbreaks have been reported in southeast Asian countries, including Myanmar, during the previous 10 years. METHODS: EV-D68 was detected in nasopharyngeal swabs from children with acute lower respiratory infections in Myanmar. The samples were previously collected from children aged 1 month to 12 years who had been admitted to the Yankin Children Hospital in Yangon, Myanmar, between May 2017 and January 2019. EV-D68 was detected with a newly developed EV-D68-specific real-time PCR assay. The clade was identified by using a phylogenetic tree created with the Bayesian Markov chain Monte Carlo method. RESULTS: During the study period, nasopharyngeal samples were collected from 570 patients. EV-D68 was detected in 42 samples (7.4 %)-11 samples from 2017 to 31 samples from 2018. The phylogenetic tree revealed that all strains belonged to clade B3, which has been the dominant clade worldwide since 2014. We estimate that ancestors of currently circulating genotypes emerged during the period 1980-2004. CONCLUSIONS: To our knowledge, this is the first report of EV-D68 detection in children with acute lower respiratory infections in Yangon, Myanmar, in 2017-2018. Detection and detailed virologic analyses of EV-D68 in southeast Asia is an important aspect of worldwide surveillance and will likely be useful in better understanding the worldwide epidemiologic profile of EV-D68 infection.

An outbreak investigation of parechovirus-A3 in a newborn nursery.

OBJECTIVE: To investigate parechovirus-A3 (PeV-A3) transmission in a newborn nursery, after encountering 3 neonates with fever and rash. DESIGN: An observational study. SETTING: At a newborn nursery at the general hospital in Hyogo, Japan. PARTICIPANTS: Symptomatic neonates and their family members, and asymptomatic neonates born during the same period. METHODS: PCR assays for PeV-A and genotyping were used for the investigation of PeV-A3. Preserved umbilical cords were used to identify the route of transmission. RESULTS: PeV-A3 infection was confirmed in the three symptomatic neonates. The index case had fever and rash, and the 2 neonates treated later became symptomatic and had serum, cerebrospinal fluid, and stool specimens that were positive for PeV-A3 on PCR. The umbilical cord of the index case was positive for PeV-A3 on PCR. The family members of the index case, including the mother, were asymptomatic before delivery. The older sister and cousin of the PeV-A3-infected neonate had positive PCR results. The sequence analysis suggested 2 possible transmission routes: vertical and horizontal transmission in a newborn nursery and/or a family outside the hospital. The incubation period of PeV-A3 infection was estimated to be 1-3 days (maximum, 7 days). CONCLUSION: Horizontal transmission of PeV-A3 was confirmed in a newborn nursery. Vertical transmission was suggested by the detection of RNA in an umbilical cord sample from the index case. These observations indicate that PeV-A3 can be horizontally transmitted in a newborn nursery and that special caution is required to prevent healthcare-associated transmission of PeV-A3.

GPATCH4 contributes to nucleolus morphology and its dysfunction impairs cell viability.

The nucleolus serves a multifaceted role encompassing not only rRNA transcription and ribosome synthesis, but also the intricate orchestration of cell cycle regulation and the modulation of cellular senescence. G-patch domain containing 4 (GPATCH4) stands as one among the nucleolar proteins; however, its functional significances remain still unclear. In order to elucidate the functions of GPATCH4, we examined the effects of its dysfunction on cellular proliferation, alterations in nucleolar architecture, apoptotic events, and cellular senescence. Through experimentation conducted on cultured neuroblastoma SH-SY5Y cells, the reduction of GPATCH4 caused inhibition of cellular proliferation, concurrently fostering escalated apoptotic susceptibilities upon exposure to high-dose etoposide. In the realm of nucleolar morphology comparisons, a discernible decline was noted in the count of nucleoli per nucleus, concomitant with a significant expansion in the area occupied by individual nucleoli. Upon induction of senescence prompted by low-dose etoposide, GPATCH4 knockdown resulted in decreased cell viability and increased expression of senescence-associated markers, namely senescence-associated ß-galactosidase (SA-ß-GAL) and p16. Furthermore, GPATCH4 dysfunction elicited alterations in the gene expression profile of the ribosomal system. In sum, our findings showed that GPATCH4 is a pivotal nucleolar protein that regulates nucleolar morphology and is correlated with cell viability.

Incidence of Omicron Variant Reinfection and Reduction of Reinfection Risk After Coronavirus Disease 2019 Vaccination in Children.

Data are limited on the incidence of coronavirus disease 2019 (COVID-19) reinfection in children. This population-based cohort study in Niigata, Japan from January to November 2022 demonstrated the incidence of reinfection was 1337/48 099 (2.8%), and the hazard ratio for reinfection in vaccinated children was 0.29 (95% confidence interval, 0.20-0.40).

Human Rhinovirus as a Cause of Fever in Neonates and Young Infants During the COVID-19 Pandemic, 2020-2022.

BACKGROUND: Human rhinovirus (HRV) was predominant and persistent during the coronavirus disease 2019 (COVID-19) pandemic despite nonpharmaceutical interventions. The data whether HRV persistence also occurred in neonates and young infants were very limited. METHODS: This prospective observational study was conducted in Niigata, Japan, between January 2020 and September 2022. The participants were hospitalized neonates and infants aged less than 4 months with fever. We excluded patients with evidence of bacterial infection or obvious sick contact with influenza or respiratory syncytial virus infection, as confirmed by rapid antigen detection tests. COVID-19 diagnosed by polymerase chain reaction (PCR) or rapid antigen detection tests were also excluded. Parechovirus and enterovirus were examined by PCR using serum and/or cerebrospinal fluid. FilmArray Respiratory Panel v1.7 was conducted on nasopharyngeal swabs. If HRV was positive, the genotype was identified. RESULTS: We included 72 patients (median age, 54 days; interquartile range, 28.5-79 days), and sepsis was diagnosed in 31 (43.1%) patients. In total, 27 (37.5%) patients had had positive multiplex PCR tests. These patients were more likely to have rhinorrhea (P = 0.004), cough (P = 0.01), and sick contact (P < 0.001) than those who with negative multiplex PCR. HRV was the most frequently detected virus (n = 23, 85.2%), and species A (n = 15, 71.4%) and C (n = 6, 28.6%) were genotyped. No seasonality or monthly predominance of the specific HRV types was observed. CONCLUSIONS: HRV was an important cause of fever in neonates and young infants during the COVID-19 pandemic, 2020 to 2022.

Cord blood granulocyte Colony-Stimulating factor level as an optimal predictor of umbilical cord arteritis associated with brain injury at term equivalent age in preterm neonates.

OBJECTIVE: The study aimed 1) to evaluate the association between the presence or absence of umbilical cord arteritis (UCA) and the cord blood cytokine levels, and 2) morbidity and mortality of preterm neonates; and 3) to identify predictive markers for UCA of preterm neonates. STUDY DESIGN: In this single-center retrospective observational cohort study, preterm neonates born at gestational age (GA) < 36 weeks were categorized pathologically according to the severity of intrauterine inflammation; those without UCA as Group 1, those with UCA as Group 2, and those without any intrauterine inflammation as Group 3 (control), and subgroup analyses classified by their GA were performed. We compared morbidity and mortality, and eight representative cytokine levels in cord blood samples between the groups. Subsequently, receiver operating characteristics (ROC) curves for UCA diagnosis for each cytokine were created, and values of areas under the curve (AUC) were calculated to determine the optimal predictive markers. RESULTS: In total, 105 patients (36, 58, and 11 in Groups 1, 2, and 3, respectively) were included. Multivariate logistic analysis revealed that patients with UCA had higher incidence of brain injury (Odds Ratio [OR] = 8.53, P = 0.0049, 95% Confidence Interval [CI]: 1.91 - 38.0), at term equivalent age in the subgroup analysis with GA < 32 weeks. Although the median value of cord blood granulocyte colony-stimulating factor (G-CSF) was significantly higher in Group 2 than in Group 1 or 3, only the G-CSF level was found to be high in the subgroup analysis with GA < 32 weeks. For UCA diagnosis, the AUC values of G-CSF were the highest among eight cytokines including interleukin 6 (IL-6). These findings were similar in the subgroup analysis with GA < 32 weeks. CONCLUSIONS: Preterm neonates, especially born at GA < 32 week, had higher morbidity from　brain injury in the group with UCA. The cord blood G-CSF level was highly accurate for predicting UCA and could thus be used as an optimal biomarker.

Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022.

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.

Purulent nasal discharge due to gonococcal nasopharyngitis in a neonate.

Neonatal gonorrhea, caused by Neisseria gonorrhoeae, is an uncommon but important disease to prevent because its complications, such as gonococcal ophthalmia neonatorum causes blindness if untreated. Neonatal gonococcal nasopharyngitis is a rare, but important clinical manifestation to suspect gonococcal infection in a neonate. Herein we report a case of neonatal gonococcal nasopharyngitis, presented with purulent nasal discharge. A full-term male neonate without perinatal complications developed purulent eye discharge on the 7th day of life. N. gonorrhoeae was isolated from the eye discharge culture; however, he did not receive the standard regimen. Subsequently, he presented to our hospital with fever and nasal discharge on the 20th day of life. N. gonorrhoeae was also isolated from nasal discharge and nasopharyngeal swabs without any evidence of chlamydia or syphilis. He received intravenous cefotaxime until disseminated gonococcal infection was ruled out and was discharged without any sequelae. Rhinorrhea in newborns requires consideration of mother-to-child transmission of various microorganisms, not only common respiratory viruses, but also rare, serious preventable infections such as gonorrhea or syphilis. Along with the recent syphilis patients on the rise in Japan, gonorrhea is an important disease to recognize, and the incidence could increase. Clinical manifestations of neonatal gonococcal infections, including nasopharyngitis, need to be recognized to suspect the diagnosis and initiate appropriate treatment to prevent serious complications.

Mumps vaccine hesitancy: Current evidence and an evidence-based campaign in Japan.

BACKGROUND: Mumps is still endemic in Japan because mumps vaccination is voluntary. In this study, we investigated associations of parental socioeconomic status, family structure, and knowledge/belief about mumps and mumps vaccine with parental decision to vaccinate their children. We also evaluated effectiveness of a campaign based on survey results. METHODS: We conducted a cross-sectional survey of parents with children aged 1-6 years attending preschools or kindergartens in Tokamachi City, Japan. We assessed the association of parental factors with their decision to vaccinate their children using multivariable logistic regression analyses. We designed a campaign based on the survey results, and compared the number of annual vaccinations at Tokamachi Hospital per the child population aged 1-6 years in Tokamachi City before and after the campaign using a trend test. RESULTS: In total, 1391 of 1617 (86%) eligible parents completed the survey. Among these parents, 229 (16%) vaccinated their children. In multivariable analyses, higher parental education [odds ratio (OR) = 2.21; 95% CI, 1.59-3.08; P < 0.001], greater knowledge about mumps and the mumps vaccine (OR = 1.88; 95% CI, 1.60-2.21; P < 0.001), and living without grandparents (OR = 1.44; 95% CI, 1.05-1.99; P = 0.024) were significantly associated with parental decision to vaccinate their children. The number of annual vaccinations per the child population significantly increased following the campaign (P < 0.001). CONCLUSION: Our study showed several sociodemographic factors significantly associated with mumps vaccination. Further research is needed to examine the relevance of our findings to the uptake of other voluntary vaccines among children.

Detection of parechovirus-A in hospitalized children with acute lower respiratory infection in Myanmar, 2017-2018.

Parechovirus-A (PeV-A) causes emerging infection in children, and clinical presentation depends on genotype. The virus has been investigated mainly in developed countries; however, data from developing countries, especially in Asia, are sparse. This study investigated whether PeV-A circulated in children in Myanmar. This retrospective study evaluated PeV-A in nasopharyngeal samples from children aged 1 month to 12 years who were hospitalized with acute lower respiratory infection at Yankin Children Hospital, Yangon, Myanmar, during the period from May 2017 to April 2019. Real-time polymerase chain reaction (PCR) was used to detect PeV-A, and PCR-positive samples were used for genotyping and phylogenetic analysis. In total, 11/570 (1.9%) of samples were positive for PeV-A; 7 were successfully genotyped by sequencing the VP3/VP1 region, as follows: PeV-A1 (n = 4), PeV-A5 (n = 1), PeV-A6 (n = 1), and PeV-A14 (n = 1). Median age was 10.0 months (interquartile range 4.0-12.0 months), and other respiratory viruses were detected in all cases. Phylogenetic analysis showed that all detected PeV-A1 strains were in clade 1 A, which was a minor clade worldwide. Four PeV-A genotypes were detected in Myanmar. The clinical impact of PeV-A in children should be evaluated in future studies.

Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.