International Journal of Infectious Diseases 104 (2021) 97–101

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Clinical characteristics of pediatric febrile urinary tract infection

in Japan
Takuma Ohnishia,b,* , Yoshinori Mishimaa , Nozomi Matsudac, Daisuke Satod ,
Daisuke Uminoe , Ryuta Yonezawaf , Keiji Kinoshitag, Kikuko Tamurah , Shigenao Mimurai ,
Shohei Arijij, Naonori Maedak , Keiko Ozakil, Hiroyuki Fukushimam , Tomohiro Arakuman ,
Satoko Tsuchidao , Hajime Nishimotop , Yoshinori Arakiq , Makoto Yoshidar,
Takuya Tamames , Shigeru Suzukit , Toshio Sekijimau , Takanori Kowasev,
Kanae Takahashiw, Isamu Kamimakia
a
Department of Pediatrics, National Hospital Organization Saitama Hospital, 2-1 Suwa, Wako-shi, Saitama 351-0102, Japan
b
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
c
Department of Pediatrics, Soka Municipal Hospital, 2-21-1 Soka, Soka-shi, Saitama 340-8560, Japan
d
Department of Pediatrics, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi-shi, Saitama 332-8558, Japan
e
Tsuchiya Children’s Hospital, 3-1-10 Kukichuou, Kuki-shi, Saitama 346-0003, Japan
f
Department of Pediatrics, IMS Fujimi General Hospital, 1967-1 Tsuruma, Fujimi-shi, Saitama 354-0021, Japan
g
Department of Pediatrics, Koshigaya Municipal Hospital, 10-47-1 Higashikoshigaya, Koshigaya-shi, Saitama 343-8577, Japan
h
Department of Pediatrics, National Hospital Organization Nishisaitama-chuo National Hospital, 2-1671 Wakasa, Tokorozawa-shi, Saitama 359-1151, Japan
i
Department of Pediatrics, Ageo Central General Hospital, 1-10-10 Komaza, Ageo-shi, Saitama 362-8588, Japan
j
Department of Pediatrics, Kawaguchi Municipal Medical Center, 180 Araijuku, Kawaguchi-shi, Saitama 333-0833, Japan
k
Department of Pediatrics, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
l
Department of Pediatrics, Hino Municipal Hospital, 4-3-1 Tamadaira, Hino-shi, Tokyo 191-0062, Japan
m
Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa-shi, Chiba 272-8513, Japan
n
Department of Pediatrics, Saitama Cooperative Hospital, 1317 Kisoro, Kawaguchi-shi, Saitama 333-0831, Japan
o
Department of Pediatrics, Japanese Red Cross Akita Hospital, 222-1 Kamikitatesarutanawashirosawa, Akita-shi, Akita 010-1495, Japan
p
Department of Pediatrics, Saitama Citizens Medical Center, 299-1 Shimane, Nishi-ku, Saitama-shi, Saitama 331-0054, Japan
q
Department of Pediatric Nephrology, National Hospital Organization Hokkaido Medical Center, 5-7-1-1 Yamanote, Nishi-ku, Sapporo-shi, Hokkaido 063-
0005, Japan
r
Department of Pediatrics, Sano Kosei General Hospital, 1728 Horigome-cho, Sano-shi, Tochigi 327-8511, Japan
s
Department of Pediatrics, Saitama City Hospital, 2460 Mimuro, Midori-ku, Saitama-shi, Saitama 336-8522, Japan
t
Department of Pediatrics, Seirei Sakura Citizen Hospital, 2-36-2 Eharadai, Sakura-shi, Chiba 285-0825, Japan
u
Department of Pediatrics, Hanyu General Hospital, 446 Shimoiwase, Hanyu-shi, Saitama 348-8505, Japan
v
Department of Pediatrics, Gyoda General Hospital, 376 Mochida, Gyoda-shi, Saitama 361-0056, Japan
w
Department of Medical Statistics, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka-shi, Osaka 545-8585, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Background: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in
Received 21 November 2020 children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in
Received in revised form 7 December 2020 Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children.
Accepted 23 December 2020
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.
Keywords: The diagnostic criteria were a temperature over 38  C and the presence of a single bacterial pathogen in
Urinary tract infection
urine culture. Patient characteristics were obtained from medical records.
Enterococcus
Hydronephrosis
Results: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were
Vesicoureteral reflux 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.

* Corresponding author at: Department of Pediatrics, National Hospital Organization Saitama Hospital, 2-1 Suwa, Wako-shi, Saitama, 351-0102, Japan.
E-mail address: prince1999and7@a2.keio.jp (T. Ohnishi).

https://doi.org/10.1016/j.ijid.2020.12.066
1201-9712/© 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
T. Ohnishi et al. International Journal of Infectious Diseases 104 (2021) 97–101

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.
© 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).

Introduction
Urinary tract infections (UTI) are one of the most common
bacterial infections in children (Shaikh et al., 2008; O’Brien et al.,
2011; Hoberman et al., 1993). The majority of febrile children with
UTI have evidence of pyelonephritis (Hoberman and Wald, 1997).
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
(Jacobson et al., 1989; Round et al., 2012). 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 (Ohnishi
et al., 2019). 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 (Yamamoto et al., 2016). Patients with a negative
urine culture were also included if renal cold spots had been
identified using renal scintigraphy or contrast computed tomog-
raphy [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 (Fernbach et al., 1993). 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 (Lebowitz et al., 1985).
Our study categorized grades I to II as mild VUR, and grades III to V
as severe VUR (Peters et al., 2010). 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.

Table 1
Patient characteristics.

Total (n = 2049) First (n = 1734) Recurrent (n = 309) p-Value Missing (%)

Sex % (n) Female 40.8 (836) 39.3 (682) 48.5 (150) 0.002a 0
Male 59.2 (1213) 60.7 (1052) 51.5 (159)
Age in months (median [IQR]) 5.00 [3.00, 12.00] 5.00 [2.00, 10.00] 11.00 [5.00, 57.00] <0.001b 0
Pathogens % (n) Escherichia coli 76.6 (1570) 79.9 (1385) 59.2 (183) <0.001a 0
Enterococcus species 9.8 (200) 8.8 (153) 14.6 (45)
-E. faecalis 6.1 (126) 5.7 (99) 8.4 (26)
-E. faecium 0.1 (3) 0.1 (1) 0.6 (2)
Klebsiella species 5.2 (106) 5.0 (86) 5.8 (18)
-K. pneumoniae 3.2 (66) 2.9 (51) 4.2 (13)
-K. oxytoca 1.9 (38) 2.0 (34) 1.3 (4)
Enterobacter species 1.6 (32) 1.0 (17) 4.9 (15)
Citrobacter species 0.8 (16) 0.7 (12) 1.3 (4)
Proteus mirabilis 0.4 (8) 0.3 (5) 1.0 (3)
Pseudomonas aeruginosa 1.2 (24) 0.2 (3) 6.8 (21)
Others 5.5 (93) 4.2 (73) 6.5 (20)
Bacteremia % (n) 2.2 (46) 2.2 (39) 2.3 (7) 0.986a 0
Hydronephrosis_Grade % (n) None 65.1 (1199) 66.1 (1049) 58.6 (147) 0.121a 10.1
I 18.9 (348) 18.6 (295) 21.1 (53)
II 4.6 (85) 4.2 (66) 7.2 (18)
III 1.1 (20) 0.9 (15) 2.0 (5)
IV 0.5 (9) 0.4 (7) 0.8 (2)
V 0.1 (2) 0.1 (2) 0.0 (0)
Uncertain grade 9.7 (179) 9.6 (153) 10.4 (26)
VUR_severity % (n) None 59.1 (761) 64.6 (676) 35.1 (84) <0.001a 37.2
Mild 14.1 (181) 13.1 (137) 18.0 (43)
Severe 22.7 (292) 19.8 (207) 35.6 (85)
Uncertain severity 4.1 (53) 2.5 (26) 11.3 (27)

Abbreviation: VUR, vesicoureteral reflux.

a
Chi-squared test.
b
Wilcoxon rank sum test.

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T. Ohnishi et al. International Journal of Infectious Diseases 104 (2021) 97–101

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 institu-
tional review board. Consent was obtained using an opt-out
procedure.

Data collection

All of the coinvestigators were pediatricians. Each coinvestiga-

tor 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
Figure 1. Frequency of febrile urinary tract infection by age and sex.
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 continu-
ous 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 Comput-
ing, 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%.
Figure 2. Frequency of febrile urinary tract infection by age in months (<24
months) and sex.
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).
Hydronephrosis and the prediction of VUR
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.
Discussion
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 (Schnadower
et al., 2010), 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.

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T. Ohnishi et al.
Table 2
A comparison of the clinical features between children with first fUTI by E. coli and Enterococcus.
E. coli
Sex, male % (n) 58.8
Age in months (median [IQR]) 4 [2, 9]
VUR per VCUG % (n) 30.3
Hydronephrosis % (n) 34.4
Antibiotic therapy in the previous month % (n) 6.2
Abbreviation: VUR, vesicoureteral reflux; VCUG, voiding cystourethrography; E. coli, Eschelichia coli.
a
Chi-squared test.
b
Wilcoxon rank sum test.
Table 3
Power of detecting vesicoureteral reflux by renal bladder ultrasonography.
VUR
Hydronephrosis 170
Mild VUR 52
Non-hydronephrosis 186
Mild VUR 81
Total 356
Sensitivity: 47.8% (170/356), specificity: 63.1% (410/650).
Abbreviation: VUR, vesicoureteral reflux.
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 (Jerardi and
Jackson, 2020). 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 (Hayashi et al.,
2010); because bacteria preferentially colonize the preputium and
can spread to the urethral meatus, phimosis becomes a major risk
factor for fUTI during infancy (Rushton and Majd, 1992; Hiraoka
et al., 2002). Circumcision of the prepuce decreases meatal
contamination and has been found to decrease the incidence of
UTI in infants from 1/4 to 1/20 (To et al., 1998; Wiswell et al., 1985).
However, the circumcision of infants is seldom performed in Japan
(Hayashi et al., 2010). It is plausible that the male predominance
diminishes with age because the prepuce gradually becomes
retractable (Gairdner, 1949).
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 (Finnell et al., 2011;
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 (Chandra et al., 1996). However,
other reports have shown that the incidence of VUR is very similar
between the groups: 17–34% in females with UTI and 18–45% in
males (National Collaborating Centre for Women’s and Children’s
Health, 2007). 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. (Schnadower et al., 2010). Enterococcus spp.
only rarely cause cystitis and pyelonephritis in otherwise healthy
children (McNeil, 2019), although an increasing incidence of
community-acquired UTI caused by Enterococcus spp. has been
reported in some centers (Felmingham et al., 1992). In a study
conducted in Texas in the United States, Enterococcus faecalis was
International Journal of Infectious Diseases 104 (2021) 97–101
(n = 1385) Enterococcus (n = 153) p-Value
(814) 73.2 (112) 0.001a
4 [2, 24] 0.561b
(262/864) 57.3 (43/75) <0.001a
(450/1308) 30.0 (33/110) 0.406a
(64/1031) 18.8 (21/112) <0.001a
No VUR Total
240 410
Severe VUR 94 Unknown Grade 20
410 596
Severe VUR 99 Unknown Grade 6
650 1006
the second most common cause of UTI in febrile infants younger
than 60 days, accounting for 9.4% of infections (Cantey et al., 2015).
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 (Marcus et al., 2012). 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 cephalospo-
rin (Subcommittee on Urinary Tract Infection, 2011; Strohmeier
et al., 2014). 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 (Fel-
mingham et al., 1992; Marcus et al., 2012). 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
(Schnadower et al., 2010). The rate of concomitant bacteremia in
fUTI varies from 5.6% to 31%, depending on the location and the
patient cohort (Schnadower et al., 2010; Pitetti and Choi, 2002).
One of the main risk factors for bacteremia in pediatric UTI is young
age (Yoon et al., 2020), 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 (Subcommittee on Urinary Tract
Infection, 2011). 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
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T. Ohnishi et al.
have high-grade VUR (Subcommittee on Urinary Tract Infection,
2016). 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 (Kimata et al., 2013). 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 (Kimata
et al., 2013; Massanyi et al., 2013).
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
Supplementary material related to this article can be found, in
the online version, at doi:https://doi.org/10.1016/j.
ijid.2020.12.066.
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