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Department of Pediatrics, National Hospital Organization Saitama Hospital, 2-1 Suwa, Wako-shi, Saitama 351-0102, JapanDepartment of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Department of Pediatric Nephrology, National Hospital Organization Hokkaido Medical Center, 5-7-1-1 Yamanote, Nishi-ku, Sapporo-shi, Hokkaido 063-0005, Japan
This is the first study describing the clinical picture of pediatric fUTI in Japan.
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Febrile UTI has significant male predominance in Japanese infants.
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E. coli was the first, and Enterococcus was the second most frequent pathogen in fUTI.
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Enterococcus had a higher rate of VUR and recent antibiotic use than E. coli.
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The sensitivity of detecting VUR with hydronephrosis was 47.8%.
Abstract
Background
Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children.
Methods
A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records.
Results
In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively.
Conclusions
There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.
). Because febrile UTI (fUTI) can result in renal scarring and the associated long-term complications (i.e., hypertension and chronic kidney disease), prompt diagnosis and treatment are crucial (
). Understanding the features of patients with fUTI is important in order to identify and diagnose fUTI in clinical practice. Previously, there have not been any multicenter studies in Japan on the clinical characteristics of pediatric fUTI. Although Japanese pediatricians use data from the United States and Europe as a clinical reference, it was pointed out by a single-center study that Japan may have a different sex ratio and age distribution for fUTI compared to other countries (
). This study aimed to address this issue by clarifying the clinical characteristics of fUTI in Japanese children.
Methods
Study design and setting
This study formed part of a multisite, retrospective chart review of children with fUTI in an acute care setting (emergency department and/or general pediatric outpatient clinic) in 21 Japanese hospitals from January 1, 2008 to December 31, 2017, or as far back as the medical records could be checked. All of the sites were located in eastern Japan, as detailed in the Supplementary Table.
Case definition and study population
Patients under the age of 16 years were included in the study who had been diagnosed with fUTI based on the criteria used in Japanese guidelines: a temperature of at least 38 °C and a single pathogen (≥104 colony-forming units/mL for catheter specimens or ≥105 colony-forming units/mL for clean-catch specimens) in urine culture (
). Patients with a negative urine culture were also included if renal cold spots had been identified using renal scintigraphy or contrast computed tomography [CT]. Urine specimens had been obtained either by bladder catheterization or by the midstream clean-catch method. Patients with hydronephrosis had been diagnosed using renal bladder ultrasonography (RBUS), CT, or magnetic resonance imaging (MRI), and were classified as grade I to V according to the Society for Fetal Urology Classification (
). Patients with vesicoureteral reflux (VUR) had been diagnosed using voiding cystourethrography (VCUG) and classified as grade I to V according to the International Reflux Classification (
). Bacteremia was defined as the growth of a pathogen in the blood culture. In the current study, we counted one patient per episode, even if the same patient had more than one episode of fUTI.
Study protocol
The study was approved by the Institutional Medical Ethics Committee of the National Hospital Organization Saitama Hospital (R2018-11). The study was also approved by each site’s institutional review board. Consent was obtained using an opt-out procedure.
Data collection
All of the coinvestigators were pediatricians. Each coinvestigator examined the medical charts for the patients at their site. The relevant data was entered into a Microsoft Excel spreadsheet and sent to a central database.
The information collected included the patient demographics, the number of previous UTIs, any complications of bacteremia, the causative pathogens, and antimicrobial use within the previous month. The grades of hydronephrosis and VUR were also recorded when relevant.
Outcomes
Patients were divided into two groups: first-episode fUTI and recurrent fUTI. Patients were excluded if it was not known whether the fUTI was a first episode. The characteristics of the two groups were compared, and a comparison was also carried out between first-episode fUTIs caused by E. coli and Enterococcus spp. Further tests determined the whether hydronephrosis could predict the presence of VUR in patients with a first-episode fUTI.
Statistical analyses
The patient characteristics were summarized as frequencies and percentages for the categorical variables, and as medians and interquartile ranges for the continuous variables. The statistical significance was determined using the Chi-squared test for the categorical data and the Wilcoxon rank-sum test for the continuous data. p < 0.05 was considered to be statistically significant. All of the statistical analyses were performed using R Statistical Software (version 3.4.4; The R Foundation for Statistical Computing, Vienna, Austria).
Results
Study population and patient characteristics
Over the study period, a total of 2049 patients were diagnosed with fUTI. Of these, 1734 (84.6%) had a first episode and 309 (15.1%) had recurrent fUTI (Table 1). The median age was 5 months. For the male patients, 87.0% were found to be younger than 12 months, whereas this was 53.2% for the female patients (Figure 1). Beyond 12 months, infections in females gradually became more common than infections in males (Figure 2). The prevalence of VUR in patients with a first episode of fUTI was 35.4% (34.3% in males and 37.2% in females). The three most frequent causative pathogens in patients with a first-episode of fUTI were Escherichia coli (E. coli), Enterococcus spp., and Klebsiella spp., accounting for 76.6%, 9.8%, and 5.2% of the pathogens, respectively. In recurrent fUTI cases, the most frequent causative pathogens were E. coli, Enterococcus spp., and Pseudomonas spp., accounting for 59.2%, 14.6%, and 6.8% of the pathogens, respectively. The prevalence of bacteremia in all patients was 2.2%; in patients younger than 2 months the prevalence was 5.7%, and in patients between the ages of 2 months and 36 months it was 2.0%.
First-episode fUTI caused by E. coli or Enterococcus spp
A comparison was carried out between patients with a first episode of fUTI caused by E. coli and those with a first episode caused by Enterococcus spp. The demographic features and clinical observations are shown in Table 2. The infections caused by Enterococcus spp. showed a more marked male predominance compared with E. coli (73.2% vs. 58.8%, p = 0.001), a higher prevalence of VUR (57.3% vs. 30.3%, p < 0.001), and more frequent recent antibiotic use (18.8% vs. 6.2%, p < 0.001).
Table 2A comparison of the clinical features between children with first fUTI by E. coli and Enterococcus.
Table 3 shows the number of patients with first-episode fUTI (1006 in total) who were evaluated hydronephrosis and/or VUR. Analyses showed that the presence of hydronephrosis could predict VUR with a sensitivity and specificity of 47.8% and 63.1%, respectively.
Table 3Power of detecting vesicoureteral reflux by renal bladder ultrasonography.
This study analyzed data from 2049 pediatric fUTI patients in Japan. The results showed a significant male predominance for fUTI, especially in infants. Enterococcus spp., which have been identified as minor pathogens in previous studies (
), were found to be the second most frequently observed causative pathogen in Japan. To the best of our knowledge, this is the first multicenter study of pediatric fUTI in Japan.
In this study, the male-to-female ratio was 2.4:1 during the first year of life. The Nelson Textbook of Pediatrics, in contrast, gives a male-to-female ratio of 1:1.9 for this age group (
in: Kliegman R.M. St Geme J.W. Blum N.J. Shah S.S. Tasker R.C. Wilson K.M. Nelson textbook of pediatrics. 21st ed. Elsevier,
Philadelphia2020: 2789-2795
). There could be a few reasons for this male predominance observed in Japan. The most likely reason is the high prevalence of phimosis among Japanese males (
); because bacteria preferentially colonize the preputium and can spread to the urethral meatus, phimosis becomes a major risk factor for fUTI during infancy (
VUR is also one of the major risk factors for fUTI in children. Previous reports outside of Japan have documented the prevalence of VUR at 8–40% among children with UTI (
; National Collaborating Centre for Women’s and Children’s Health, 2007). Most studies, including those with the largest sample sizes, have shown rates between 20% and 38%. VUR was thought to be more common in males than in females because of a transient urodynamic dysfunction of infancy (
). In this study, the prevalence of VUR in patients with a first episode of fUTI was 34.3% in males and 37.2% in females; there was no significant sex difference. However, VCUG was not performed for all patients, and therefore, the reported prevalence may be subject to a selection bias.
Enterococcus spp. are the among the most common causative pathogens in Japan. In general, the most common bacterial species responsible for primary and recurrent UTI are E. coli, Klebsiella spp., and Enterobacter spp. (
). In a study conducted in Texas in the United States, Enterococcus faecalis was the second most common cause of UTI in febrile infants younger than 60 days, accounting for 9.4% of infections (
). A study conducted in Israel found that Enterococcus spp. accounted for 5.6% of community-acquired UTI and that, as in our study, the male predominance was more marked compared to Gram-negative bacteria (
). Our study also showed that VUR and recent antibiotic use were higher in patients with Enterococcus spp. than in those with E. coli.
Because E. coli and Klebsiella are the predominant causative agents of UTI, cephalosporins are often the recommended first-line treatment, although Enterococcus spp. are resistant to cephalosporin (
Steering Committee on Quality Improvement Management
Roberts K.B.
Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
). Gram staining enables the rapid differentiation of causative bacteria so that the correct antibiotic can be selected. For instance, E. coli and Klebsiella are Gram negative, whereas Enterococcus spp. are Gram positive. If Gram staining is not possible within a short time frame, ampicillin-sulbactam or amoxicillin-clavulanate could be used, as they can treat both Enterococcus spp. and Gram-negative bacterial infections (
). In our study, the frequency of E. coli infections was found to be lower in patients with recurrent infections than in those with a first-episode of fUTI, whereas the rate of Pseudomonas infections was much higher. Anti-pseudomonal antibiotics should therefore be considered as an empirical therapy in certain serious cases.
Patients with fUTIs complicated by bacteremia are at a higher risk of adverse outcomes, such as prolonged admission, septic shock, bacterial meningitis, and intensive care unit admission (
), and in the current study, the rate of bacteremia decreased with age.
According to the UTI guidelines of the American Academy of Pediatrics, VCUG should not be performed routinely after the first episode of fUTI, but it is indicated if RBUS reveals hydronephrosis or other abnormal findings (
Steering Committee on Quality Improvement Management
Roberts K.B.
Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
). However, concerns have been raised over the effectiveness of RBUS for detecting VUR, as it is frequently found to be normal in infants with low-grade VUR and even in some who have high-grade VUR (
Reaffirmation of AAP clinical practice guideline: the diagnosis and management of the initial urinary tract infection in febrile infants and young children 2-24 months of age.
). Indeed, one study suggested that around 50% of pediatric UTI patients who show no signs of abnormalities using RBUS, nevertheless have a high-grade VUR (
). In our study, we determined how well hydronephrosis was able to predict VUR in children with a first-episode of fUTI. The analyses revealed a sensitivity of 47.8% and and specificity 63.1%. We also observed that 51.3% of patients with severe VUR did not show hydronephrosis. As previously mentioned, because VCUG was not performed for all of the patients, the results may have been affected by a selection bias. However, the findings are consistent with previous studies, which showed that RBUS has poor sensitivity for detecting VUR (
This study also had other limitations. For instance, selection bias may have arisen because patients in local healthcare clinics were not included. Some school-age children with fUTI may be treated in such clinics without a urine culture, and so these patients would have been missed.
Conclusion
This is the first study to describe the clinical characteristics of pediatric fUTI in Japan. It was found that the patients were mainly infants, with a significant male predominance. Enterococcus spp. was found to be the second most frequently observed causative pathogen; therefore we strongly recommend performing Gram staining of urine samples before starting empirical antibiotic therapy.
Financial and funding disclosure
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Potential conflicts of interest
The authors have no conflicts of interest relevant to this article to disclose.
Acknowledgments
The authors would like to thank Editage (www.editage.jp) for English language editing.
Appendix A. Supplementary data
The following is Supplementary data to this article:
in: Kliegman R.M. St Geme J.W. Blum N.J. Shah S.S. Tasker R.C. Wilson K.M. Nelson textbook of pediatrics. 21st ed. Elsevier,
Philadelphia2020: 2789-2795
Steering Committee on Quality Improvement Management
Roberts K.B.
Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
Reaffirmation of AAP clinical practice guideline: the diagnosis and management of the initial urinary tract infection in febrile infants and young children 2-24 months of age.
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