Commensal consortia decolonize Enterobacteriaceae via ecological control.

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.

Assessing clinical benefits of live-attenuated vaccination in post-liver transplant patients: Analysis of breakthrough infections and natural boosters.

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.

Catheter-associated urinary tract infection and urinary tract abnormalities in young children: A retrospective study.

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.

Recent trends in pediatric bacterial meningitis in Japan, 2016-2018 - S. agalactiae has been the most common pathogen.

BACKGROUND: Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugated vaccine (PCV) have been widely used since 2010 in Japan. The overall incidence of bacterial meningitis decreased thereafter. Streptococcus agalactiae has become the main organism. OBJECTIVES: The purpose of the present study was to investigate the incidence rate per 1000 admissions of bacterial meningitis and the change in causative organisms in subsequent years. METHODS: A cross-sectional, multicenter, non-interventional retrospective study regarding pediatric bacterial meningitis was conducted in Japan in 2019. We analyzed the epidemiological and clinical data for 2016-2018, and compared the information obtained in our previous nationwide survey database. We also investigated the risk factors for disease outcome. RESULTS: In the 2016-2018 surveys, 197 patients from 153 hospitals from all prefectures were evaluated. S. agalactiae (0-3 months, 39%), Streptococcus pneumoniae (2-112 months, 20%), and E. coli (0-136 months, 13%) were the main organisms. The total number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.00 to 1.68 in 2000-2010 to 0.38 in 2013-2015, bu remained stable thereafter (0.35-0.40 in 2016-2018). Only one case with Neisseria meningitidis was reported. Nine cases with death were reported, including four cases with S. agalactiae. Risk factors for death and sequelae were consciousness disturbance, duration of convulsion, low CSF glucose levels, and disuse of dexamethasone (p < 0.05). CONCLUSIONS: The incidence in pediatric bacterial meningitis remained low, and S. agalactiae remains the most common cause of bacterial meningitis in Japan since 2012. S. pneumoniae is the most common cause after 3 months of age.

Effectiveness of inactivated influenza vaccine in children during the 2023/24 season: The first season after relaxation of intensive COVID-19 measures.

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.

Extended-Spectrum ß-Lactamase-Producing Escherichia coli in Neonates and Listeria monocytogenes in Young Children with Bacterial Meningitis in Japan.

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 ß-lactamase-producing-producing Escherichia coli in neonates and Listeria monocytogenes in children older than 1 month.

Pneumocystis jirovecii pneumonia after CD4+ T-cell recovery subsequent to CD19-targeted chimeric antigen receptor T-cell therapy: A case report and brief review of literature.

BACKGROUND: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy involves administration of patient-derived T cells that target B cells, resulting in B-cell depletion and aplasia. In immunity against Pneumocystis jirovecii (Pj), CD4+ T cells and, more recently, B cells, are generally considered important. Antigen presentation by B cells to CD4+ T cells is particularly important. Trimethoprim-sulfamethoxazole (TMP/SMX) for Pj pneumonia (PJP) prophylaxis is generally discontinued when the CD4+ T-cell count is >200/µL. Here we report the first case, to our knowledge, of PJP in a patient with a CD4+ T cell count of >200/µL after CAR-T cell therapy. CASE: A 14-year-old girl developed hemophagocytic lymphohistiocytosis (HLH) after cord blood transplantation (CBT) for relapsed precursor B-cell acute lymphoblastic leukemia (B-ALL). Twenty-one months after CBT, she was diagnosed with combined second relapse in the bone marrow and central nervous system. The patient was treated with CD19-targeted CAR-T cell therapy for the relapse. After CAR-T cell therapy, the patient remained in remission and continued to receive TMP/SMX for PJP prophylaxis. Seven months after CAR-T cell therapy, CD4+ T cells recovered and TMP/SMX was discontinued. The B-cell aplasia persisted. Ten months after CAR-T cell therapy, the patient developed PJP. The patient was also considered to have macrophage hyperactivation at the onset of PJP. Treatment with immunoglobulin, TMP/SMX, and prednisolone was initiated, and the patient's symptoms rapidly ameliorated. CONCLUSION: The patient in the present case developed PJP despite a CD4+ T-cell count of >200/µL after CAR-T cell therapy, probably because of inadequate CD4+ T-cell activation caused by B-cell depletion after CAR-T cell therapy and repeated abnormal macrophage immune responses after CBT. It is important to determine the duration of TMP/SMX for prophylaxis after CAR-T cell therapy according to each case, as well as the CD4+ T-cell count.

Effectiveness of inactivated influenza and COVID-19 vaccines in hospitalized children in 2022/23 season in Japan - The first season of co-circulation of influenza and COVID-19.

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.

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.

Rationally-defined microbial consortia suppress multidrug-resistant proinflammatory Enterobacteriaceae via ecological control.

Persistent colonization and outgrowth of pathogenic organisms in the intestine may occur due to long-term antibiotic usage or inflammatory conditions, which perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, though an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. In this study, we rationally isolated and down-selected commensal bacterial consortia from healthy human stool samples capable of strongly and specifically suppressing intestinal Enterobacteriaceae. One of the elaborated consortia, consisting of 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby reestablishing colonization resistance and alleviating antibiotic-resistant Klebsiella-driven intestinal inflammation in mice. Harnessing these microbial activities in the form of live bacterial therapeutics may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant bacterial infection.

Trends in effectiveness of inactivated influenza vaccine in children by age groups in seven seasons immediately before the COVID-19 era.

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.