論文 - 古市　宗弘

Risk factors in pediatric hospitalization for influenza A and B during the seven seasons immediately before the COVID-19 era in Japan

Shinjoh M., Furuichi M., Narabayashi A., Kamei A., Yoshida N., Takahashi T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy）  27 （ 12 ） 1735 - 1742 2021年12月

ISSN  1341321X

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Introduction: The risk factors in pediatric influenza immediately before the COVID-19 era are not well understood. This study aims to evaluate the risk factors for hospitalization in pediatric influenza A and B for the recent seasons. Methods: Children with a fever of ≥38 °C and laboratory-confirmed influenza at 20 hospitals in outpatient settings in Japan in the 2013/14 to 2019/20 seasons were retrospectively reviewed. Possible risk factors, including gender, age, comorbidities, nursery school or kindergarten attendance, earlier diagnosis, no immunization, lower regional temperature, earlier season, and period of onset, were evaluated using binary logistic regression methods. Results: A total of 13,040 (type A, 8861; B, 4179) children were evaluated. Significant risk factors (p < 0.05) in multivariate analyses were young age, lower regional temperature, earlier season, respiratory illness (adjusted odds ratio [aOR]:2.76, 95% confidence interval [CI]:1.84–4.13), abnormal behavior and/or unusual speech (aOR:2.78, 95% CI:1.61–4.80), and seizures at onset (aOR:16.8, 95% CI:12.1–23.3) for influenza A; and young age, lower regional temperature, respiratory illness (aOR:1.99, 95% CI:1.00–3.95), history of febrile seizures (aOR:1.73, 95% CI:1.01–2.99), and seizures at onset (aOR:9.74, 95% CI:5.44–17.4) for influenza B. Conclusions: In addition to previously known factors, including young age, seizures, and respiratory illness, abnormal behavior and/or unusual speech and lower regional temperature are new factors. Negative immunization status was not a risk factor for hospitalization. A better understanding of risk factors may help improve the determination of indications for hospitalization during the future co-circulation of influenza and COVID-19.

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Influenza vaccine effectiveness against influenza A in children based on the results of various rapid influenza tests in the 2018/19 season

Shinjoh M., Sugaya N., Yamaguchi Y., Ookawara I., Nakata Y., Narabayashi A., Furuichi M., Yoshida N., Kamei A., Kuramochi Y., Shibata A., Shimoyamada M., Nakazaki H., Maejima N., Yuasa E., Araki E., Maeda N., Ohnishi T., Nishida M., Taguchi N., Yoshida M., Tsunematsu K., Shibata M., Hirano Y., Sekiguchi S., Kawakami C., Mitamura K., Takahashi T.

PLoS ONE （PLoS ONE）  16 （ 3 March ） e0249005 2021年03月

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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.

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A novel screening method for pediatric urinary tract infection using ordinary diapers

Ohnishi T., Asada N., Furuichi M., Sekiguchi S., Awazu M., Hori N., Kamimaki I.

Scientific Reports （Scientific Reports）  10 （ 1 ） 19342 2020年12月

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Urinary tract infection (UTI) is one of the most common bacterial infections in children. The symptoms of UTI in young children are nonspecific, therefore urine should be examined whenever UTI cannot be ruled out. In clinical settings, however, collecting urine from children who are not toilet trained is sometimes difficult, presenting a challenge in UTI management. Here, we developed a “diaper UTI test”, which enables the quick detection of pyuria in ordinary diapers, and investigated its sensitivity and specificity in a clinical study. The diaper UTI test is based on a leukocyte esterase reaction. Reagent was prepared in liquid form so that it can be absorbed by disposable diapers, where it will produce a violet color in the presence of pyuria. For the clinical study, we enrolled children younger than 3 years with potential UTI who underwent bladder catheterization for urine culture and urinalysis. Of the 65 children included, 21 were diagnosed with UTI. The sensitivity and specificity of the diaper UTI test were 90.5% (95% CI 69.6–98.8) and 93.2% (95% CI 81.3–98.6), respectively. Because of its convenience and good sensitivity, the diaper UTI test may be useful in the screening of pediatric UTI.

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

Shinjoh M., Yamaguchi Y., Furuichi M., Yaginuma M., Takahashi T., Iwata S.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy）  26 （ 10 ） 1033 - 1041 2020年10月

ISSN  1341321X

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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.

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Microbiota modulate sympathetic neurons via a gut–brain circuit

Muller P.A., Schneeberger M., Matheis F., Wang P., Kerner Z., Ilanges A., Pellegrino K., del Mármol J., Castro T.B.R., Furuichi M., Perkins M., Han W., Rao A., Picard A.J., Cross J.R., Honda K., de Araujo I., Mucida D.

Nature （Nature）  583 （ 7816 ） 441 - 446 2020年07月

ISSN  00280836

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Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content1, regulating both physiological intestinal functions such as nutrient absorption and motility2,3, and brain-wired feeding behaviour2. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology4. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut–brain circuit.

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Effectiveness of inactivated influenza vaccine in children by vaccine dose, 2013–18

Shinjoh M., Sugaya N., Furuichi M., Araki E., Maeda N., Isshiki K., Ohnishi T., Nakamura S., Yamada G., Narabayashi A., Nishida M., Taguchi N., Nakata Y., Yoshida M., Tsunematsu K., Shibata M., Munenaga T., Hirano Y., Ookawara I., Sekiguchi S., Kobayashi Y., Yamaguchi Y., Yoshida N., Mitamura K., Takahashi T.

Vaccine （Vaccine）  37 （ 30 ） 4047 - 4054 2019年07月

ISSN  0264410X

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Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. Methods: VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. Results: In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. Conclusions: Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

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Regional outbreak of community-associated methicillin-resistant Staphylococcus aureus ST834 in Japanese children

Uehara Y., Sasaki T., Baba T., Lu Y., Imajo E., Sato Y., Tanno S., Furuichi M., Kawada M., Hiramatsu K.

BMC Infectious Diseases （BMC Infectious Diseases）  19 （ 1 ） 35 2019年01月

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Background: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection has recently become a challenging problem worldwide and in Japan. We experienced 10 pediatric patients infected with CA-MRSA and hospitalized from 2011 to 2014 in a tertiary care hospital in Saitama, Japan, and assessed the characteristic of the strains using a whole genome sequencing (WGS)-based approach. Methods: CA-MRSA strains isolated from infected patients who required hospitalization for treatment were evaluated in this study. Antimicrobial susceptibility tests, molecular typing by PCR and pulse-field gel electrophoresis (PFGE) were performed to characterize MRSA strains. WGS was performed for detailed genetic analysis. Results: A total of 582 MRSA strains (35.2%) were identified among 1625 S. aureus strains collected during the study period. Ten MRSA strains (1.7%) were defined as CA-MRSA clinically, and all were isolated from pediatric patients. All strains mainly caused purulent lymphadenitis, were susceptible to fluoroquinolone and tetracycline, exhibited sequence type (ST) 834 or its single-locus variants and contained staphylococcal cassette chromosome mec (SCCmec) type IVc. Phylogenic analysis by PFGE and WGS revealed close relatedness of all strains, with the number of single nucleotide polymorphisms ranging from 35 to 119 by WGS. Out of the ten strains, nine possessed the genomic island SaPISaitama2 containing tst, sec and sel genes. SaPISaitama2 comprises a mosaic of genomic islands SaPIm4 and SaPIm1 harbored by a hospital-associated MRSA strain Mu50. Conclusions: This study describes a regional outbreak of ST834-related CA-MRSA in children with a unique pathogenicity island in Japan. Pediatric patient tropism of this clone could be enhanced by susceptibility to fluoroquinolones and tetracyclines, which cannot be prescribed to children.

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Infectious Diseases Consultation Improves Treatment and Decreases Mortality by Enterococcal Bacteremia in Children

Furuichi M., Furuichi M., Horikoshi Y., Miyairi I.

Pediatric Infectious Disease Journal （Pediatric Infectious Disease Journal）  37 （ 9 ） 856 - 860 2018年09月

ISSN  08913668

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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.

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Adverse economic impact associated with blood culture contamination in a pediatric emergency department

Murofushi Y., Furuichi M., Shoji K., Kubota M., Ishiguro A., Uematsu S., Gai R., Miyairi I.

Pediatric Infectious Disease Journal （Pediatric Infectious Disease Journal）  37 （ 8 ） 755 - 758 2018年08月

ISSN  08913668

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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.

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Clinical characteristics of influenza virus-induced lower respiratory infection during the 2015 to 2016 season

Uda K., Shoji K., Koyama-Wakai C., Furuichi M., Iwase N., Fujisaki S., Watanabe S., Miyairi I.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy）  24 （ 6 ） 407 - 413 2018年06月

ISSN  1341321X

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Background: Influenza A(H1N1)pdm09 virus infections often manifest severe respiratory symptoms, particularly in patients with a past history of allergic disease. Most of these findings were reported during the 2009 pandemic. The purpose of this study was to detail the clinical characteristics of influenza virus-induced lower respiratory infection (LRI) during the A(H1N1)pdm09-predominant 2015–2016 season. Methods: We retrospectively reviewed the clinical characteristics of influenza-induced LRI cases in children admitted to a tertiary children's hospital. Molecular diagnostic evaluation was performed on samples obtained from the most severe cases. Results: We identified 66 patients with influenza-associated hospitalization and included 21 patients with influenza virus-induced LRI for analyses. Twelve patients (57%) were admitted to the pediatric intensive care unit, seven (33%) required mechanical ventilation, and three (14%) required extracorporeal membrane oxygenation. Plastic bronchitis (PB) was identified in six patients (29%), among whom a past medical history of asthma or food allergy were noted in all six patients. A past history of allergic disease was more common among patients with, than among those without, PB (p = 0.009). A(H1N1)pdm09 was detected from all the PB cases, and phylogenetic analyses of the hemagglutinin and neuraminidase genes demonstrated that this virus belonged to subclades 6B.1 and 6B.2. In the six PB cases, we found one patient with H275Y mutation in neuraminidase. Conclusion: Allergic disease was a risk factor for developing PB due to influenza A(H1N1)pdm09 infection during the 2015–16 season.

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Characteristics and Risk Factors of Late-onset Bloodstream Infection beyond 6 Months after Liver Transplantation in Children

Furuichi M., Fukuda A., Sakamoto S., Kasahara M., Miyairi I.

Pediatric Infectious Disease Journal （Pediatric Infectious Disease Journal）  37 （ 3 ） 263 - 268 2018年03月

ISSN  08913668

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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.

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