Published papers

During influenza epidemics, Japanese clinicians routinely conduct rapid influenza diagnostic tests (RIDTs) in patients with influenza-like illness, and patients with positive test results are treated with anti-influenza drugs within 48 h after the onset of illness. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children (6 months–15 years old, N = 4243), using a test-negative case-control design based on the results of RIDTs in the 2018/19 season. The VE against influenza A(H1N1)pdm and A(H3N2) was analyzed separately using an RIDT kit specifically for detecting A(H1N1)pdm09. The adjusted VE against combined influenza A (H1N1pdm and H3N2) and against A(H1N1)pdm09 was 39% (95% confidence interval [CI], 30%–46%) and 74% (95% CI, 39%–89%), respectively. By contrast, the VE against non-A(H1N1)pdm09 influenza A (presumed to be H3N2) was very low at 7%. The adjusted VE for preventing hospitalization was 56% (95% CI, 16%–77%) against influenza A. The VE against A(H1N1)pdm09 was consistently high in our studies. By contrast, the VE against A(H3N2) was low not only in adults but also in children in the 2018/19 season.

Background: Bacterial meningitis remains a life-threatening condition in pediatric patients with cerebrospinal fluid (CSF) shunts. While infection prevention has been extensively studied, risk factors for severe outcomes such as death and neurological sequelae remain poorly understood. We examined the clinical characteristics of pediatric bacterial meningitis with CSF shunts, focusing on the risk factors associated with poor outcomes. Methods: This study is part of a nationwide surveillance of pediatric bacterial meningitis in Japan from 2009 to 2021. We extracted pediatric meningitis cases with CSF shunts from the database. Clinical characteristics, risk factors for poor outcomes, defined as death or severe neurological sequelae and causative organisms were assessed. Logistic regression models were used to identify significant risk factors. Results: In this study, 167 pediatric cases of bacterial meningitis with CSF shunts were included. In multivariable analysis, male sex [odds ratio (OR): 2.82, 95% confidence interval (CI): 1.00–7.96, P = 0.04] and younger age (OR: 0.98, 95% CI: 0.97–1.00, P = 0.002) were significant risk factors for poor outcomes. The most common causative organism was Staphylococcus spp. (65.9%), predominantly coagulase-negative Staphylococci (45.3%). While the reduction in Streptococcus pneumoniae and Haemophilus influenzae cases following vaccine introduction was not statistically significant, a decreasing trend was observed. Conclusion: Younger age and male sex were significant risk factors for poor outcomes. In addition, vaccination may have contributed to a decline in Streptococcus pneumoniae and Haemophilus influenzae infections.

Recently, live-attenuated measles, rubella, varicella, and mumps vaccines have been administered to carefully selected post-liver transplant patients. Although attention has been focused on post-vaccination antibody titers and adverse events, the real-life clinical benefits remain unclear. A comprehensive analysis of breakthrough infections and natural boosters (asymptomatic cases with significant elevation in virus antibody titers) following immunization post-liver transplantation was conducted from 2002-2023, exploring the timing, frequency, correlation with domestic outbreaks, and degree of antibody elevation. During the median 10-year observation period among 68 post-liver transplant patients, breakthrough infections occurred only in chickenpox, with 7 mild cases (1 episode/64 person-years). A total of 59 natural booster episodes (1, 5, 20, and 33 for measles, rubella, chickenpox, and mumps, respectively) were observed, with incidence rates of 1 per 569, 110, 22, and 17 person-years, respectively. The timing of natural boosters closely correlated with domestic outbreaks (P < .05 in chickenpox and mumps), influenced by local vaccine coverage. The degree of antibody elevation was significantly higher in individuals with breakthrough infections than in those with natural boosters (P < .05). These findings suggest that immunization with live-attenuated vaccines for post-liver transplant patients has demonstrated clinical benefits. Furthermore, mass vaccination has a positive impact on post-transplant patient outcomes.

Persistent colonization and outgrowth of potentially pathogenic organisms in the intestine can result from long-term antibiotic use or inflammatory conditions, and may perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, although an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5–7. Here we isolated and down-selected commensal bacterial consortia from stool samples from healthy humans that could strongly and specifically suppress intestinal Enterobacteriaceae. One of the elaborated consortia, comprising 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby re-establishing colonization resistance and alleviating Klebsiella- and Escherichia-driven intestinal inflammation in mice. Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection.

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1–3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.

Background: We have reported the vaccine effectiveness of inactivated influenza vaccine in children aged 6 months to 15 years between the 2013/14 and 2018/19 seasons. Younger (6–11 months) and older (6–15 years old) children tended to have lower vaccine effectiveness. The purpose of this study is to investigate whether the recent vaccine can be recommended to all age groups. Methods: The overall adjusted vaccine effectiveness was assessed from the 2013/14 until the 2020/21 season using a test-negative case-control design based on rapid influenza diagnostic test results. Vaccine effectiveness was calculated by influenza type and by age group (6–11 months, 1–2, 3–5, 6–12, and 13–15 years old) with adjustments including influenza seasons. Results: A total of 29,400 children (9347, 4435, and 15,618 for influenza A and B, and test-negatives, respectively) were enrolled. The overall vaccine effectiveness against influenza A, A(H1N1)pdm09, and B was significant (44% [95% confidence interval (CI), 41–47], 63% [95 %CI, 51–72], and 37% [95 %CI, 32–42], respectively). The vaccine was significantly effective against influenza A and B, except among children 6 to 11 months against influenza B. The age group with the highest vaccine effectiveness was 1 to 2 years old with both influenza A and B (60% [95 %CI, 55–65] and 52% [95 %CI, 41–61], respectively). Analysis for the 2020/21 season was not performed because no cases were reported. Conclusions: This is the first report showing influenza vaccine effectiveness by age group in children for several seasons, including immediately before the coronavirus disease (COVID-19) era. The fact that significant vaccine effectiveness was observed in nearly every age group and every season shows that the recent vaccine can still be recommended to children for the upcoming influenza seasons, during and after the COVID-19 era.

Introduction: Studies investigating the role of urinary tract abnormalities in the development of catheter-associated urinary tract infections (CAUTI) in young children are limited. Thus, in the present study, we aimed to determine whether there is an association between CAUTI and urinary tract abnormalities. Methods: We performed abdominal imaging studies on all patients aged <6 years with CAUTI admitted to the pediatric intensive care units (PICU) and high care unit (HCU) at Keio university or Fukuoka Children's Hospital from April 1, 2018 to July 31, 2022. Among 40 children who developed CAUTI, 13 (33 %) had abnormal urogenital images. Further, two case-control studies were conducted before and after propensity score matching, and the groups were compared using multivariable logistic regression models to analyze the effects of various factors on CAUTI development. Results: In the multivariate logistic regression models, abnormal urogenital images (OR 5.30 [95 % CI, 2.40–11.7] and OR 3.44 [95 % CI, 1.16–9.93]) and duration of catheterization >10 days (OR 2.76 [95 % CI, 1.28–5.96] and OR 3.44 [95 % CI, 1.16–9.93]) were found to be significantly associated with development of CAUTI, both before (39 cases, 459 controls) and after propensity score matching (36 cases, 72 controls). Further, CAUTI in young children in the PICU or HCU was significantly associated with imaging abnormalities of the urinary tract. Conclusions: These results suggest that not only the presence of catheters, but also urinary tract malformations may contribute to the development of CAUTI in young children.

We have analyzed the inactivated vaccine effectiveness (VE) for preventing influenza hospitalization by test-negative design in the 2022/23 season. This is the first season of co-circulation of influenza and COVID-19, and a unique period because all inpatients received COVID-19 screening. Among 536 children hospitalized with fever, none were positive for both influenza and SARS-CoV-2. The adjusted VE for preventing influenza A for all children, the 6–12-year-old group, and those with underlying diseases was 34 % (95 ％CI, −16 %–61 %, n = 474), 76 % (95 ％ CI, 21 %–92 %, n = 81), and 92 % (95 ％ CI, 30 %–99 %, n = 86), respectively. Only 1 out of 35 hospitalized cases with COVID-19, and 42 out of 429 controls, had been immunized with COVID-19 vaccine. This is the first report showing influenza VE by age group in children in this limited season. We still recommend the inactivated influenza vaccine for children based on the significant VE in subgroup analysis.

Background: The annual administration of the influenza vaccine is the most effective method for preventing influenza. We have evaluated the effectiveness of the inactivated influenza vaccine in children aged 6 months to 15 years across the seasons from 2013/2014 to 2022/2023. This study aims to investigate the effectiveness of the inactivated influenza vaccine in the 2023/2024 season, the first year following the easing of strict COVID-19 measures, and possibly the last season when only the inactivated vaccine is available on the market. Methods: Adjusted vaccine effectiveness for the 2023/2024 season was assessed using a test-negative case-control design, with results based on polymerase chain reaction and rapid influenza diagnostic tests. Vaccine effectiveness was calculated by influenza type and patient hospitalization/outpatient status. Results: A total of 1832 children were recruited. The inactivated influenza vaccine was effective in preventing both symptomatic influenza A and B in both inpatient and outpatient settings. Overall vaccine effectiveness for influenza A was 51% (95% confidence interval [CI], 23%–69%, n = 930) in inpatient settings and 54% (95%CI, 27%–71%, n = 559) in outpatient settings. For influenza B, effectiveness was 60% (95%CI, 22%–79%, n = 859) in inpatient settings and 56% (95%CI, 26%–74%, n = 558) in outpatient settings. Analysis suggested that administering two doses enhanced effectiveness specifically against influenza B. Conclusions: This is the first study to demonstrate influenza vaccine effectiveness in children after the relaxation of strict COVID-19 measures in Japan (2023/2024). We recommend the current inactivated vaccine for preventing both influenza A and B in children, with consideration for the potential use of two doses to enhance effectiveness against influenza B.

Background: Many randomized controlled trials and systematic reviews have evaluated the use of probiotics to treat acute infectious gastroenteritis. However, most probiotic species evaluated in previous large randomized controlled trials are unavailable in Japan. Our objective was to investigate the efficacy of probiotics utilized in Japan for acute gastroenteritis. Methods: The inclusion criterion was a randomized controlled study that compared probiotics with a placebo to treat children younger than 18 years with acute infectious gastroenteritis. We excluded studies that did not contain the following species available in Japan: Bifidobacterium spp., Lactobacillus acidophilus, Enterococcus faecium, Clostridium butyricum, and Bacillus subtilis and studies in low- or lower-middle-income countries. We searched PubMed, CENTRAL, and Igaku Chuo Zasshi from their inception to November 27, 2022. After the risk of bias assessment, data on diarrhea duration, number of hospitalizations, length of hospital stay, and adverse effects were extracted. Results: Fourteen studies were included in this meta-analysis. Diarrhea lasting longer than 48 h (7 articles, n = 878) was significantly lower in the probiotic group (risk ratio (RR) 0.70, 95 % confidence interval (CI) 0.59–0.83). The duration of diarrhea (14 articles; n = 1761) was 23.45 h (95 % CI 18.22–26.69) shorter in the probiotic group. Duration of hospitalization (6 articles; n = 971) was 17.73 h (95 % CI 6.9–28.56) shorter in the probiotic group. Conclusions: Although the certainty of evidence is very low, the use of probiotics for acute gastroenteritis in children may improve diarrhea approximately one day earlier. This study was registered with PROSPERO (CRD 42023405559).

Nationwide surveillance of pediatric bacterial meningitis in Japan from 2019 to 2021 revealed two uncommon situations not covered by the recommended empiric treatment that were not rare in Japan, namely, extended-spectrum β-lactamase-producing-producing Escherichia coli in neonates and Listeria monocytogenes in children older than 1 month.

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.

Background: A recent conditional recommendation suggests considering live-attenuated vaccines for solid organ transplant recipients, yet the conditions of their safe and effective administration remain unclear. Methods: This prospective study was conducted at Keio University Hospital from 2002 to August 2023. We gave a live-attenuated vaccine to liver transplant (LT) recipients fulfilling criteria for live-attenuated vaccines, including criteria for humoral and cell-mediated immunity. Patient background information, immunization date, vaccine strain, immunosuppressive agents at the time of vaccination, and antibody titers were collected. Factors related to primary and secondary vaccine failure were evaluated to enhance the effectiveness of the live-attenuated vaccine program after LT. Results: Among 67 LT recipients, 54, 55, 47, and 55 received at least one dose of live-attenuated vaccine for measles, rubella, varicella, and mumps, respectively. The difference in vaccine strains, but not the use of two or more immunosuppressive agents, was associated with a lower risk of vaccine failures. Measles vaccine with the AIK-C strain exhibited significantly lower primary and secondary failure rates than the CAM-70 strain (1/38 vs. 4/16, odds ratio: 0.08, 95 % confidence interval [CI]: 0.01–0.80, p = 0.02, and hazard ratio: 0.54, 95 % CI: 0.34–0.85, p = 0.01, respectively). No primary failures were observed with the TO-336 strain of rubella, whereas 4 of 10 LT recipients with the Matsuura strain of rubella did not seroconvert. For mumps, the Hoshino strain showed lower primary failure rates than the Torii strain (15/52 vs. 3/3, p = 0.03). Conclusion: According to a 20-year long-term study, vaccine strains are the most critical factor influencing primary and secondary vaccine failure in post-transplant live-attenuated vaccination.

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.