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Pediatr Nephrol (2014) 29:15671574

DOI 10.1007/s00467-014-2801-z

ORIGINAL ARTICLE

Comparison of procalcitonin and different guidelines for first


febrile urinary tract infection in children by imaging
Pei-Fen Liao & Min-Sho Ku & Jeng-Dau Tsai &
Yu-Hua Choa & Tung-Wei Hung & Ko-Huang Lue &
Ji-Nan Sheu

Received: 17 December 2013 / Revised: 25 February 2014 / Accepted: 26 February 2014 / Published online: 20 March 2014
# IPNA 2014

Abstract
Background We examined the ability of a procalcitonin (PCT)
protocol to detect vesicoureteral reflux (VUR) and renal scarring (RS), evaluated procedural costs and radiation burden,
and compared four representative guidelines for children with
their first febrile urinary tract infection (UTI).
Methods Children aged 2 years with their first febrile UTI
who underwent renal ultrasonography (US), acute and late
technetium-99m (99mTc)-dimercaptosuccinic acid scan, and
voiding cystourethrography were prospectively studied. The
representative guidelines applied in a retrospective simulation
included the American Academy of Pediatrics (AAP),
National Institute of Clinical Excellence, top-down approach
(TDA), and Italian Society of Pediatric Nephrology (ISPN).
These were compared in terms of ability to detect abnormalities, procedural costs and radiation.
Results Of 278 children analyzed, 172 (61.9 %) had acute
pyelonephritis. There was VUR in 101 (36.3 %) children,
including 73 (26.3 %) with grades IIIV VUR. RS was identified in 75 (27.0 %) children. To detect VUR, TDA and PCT

had the highest sensitivity for grades IV VUR (80.2 %) and


IIIV VUR (94.5 %), respectively, whereas AAP had the
highest specificity for IV VUR (77.4 %) and IIIV VUR
(78.0 %), respectively. TDA and PCT had the highest sensitivity (100 %) for detecting RS. The highest cost and radiation
dose was associated with TDA, whereas AAP had the least
expenditure and radiation exposure. By multivariate analysis,
PCT and VUR, especially grades IIIV, were independent
predictors of RS.
Conclusions There is no perfect guideline for first febrile UTI
children. The PCT protocol has good ability for detecting
high-grade VUR and RS. If based on available imaging modalities and reducing cost and radiation burden, clinical suggestions in the AAP guidelines represent a considerable
protocol.

Pei-Fen Liao and Min-Sho Ku contributed equally to this work.

Introduction

P.<F. Liao : M.<S. Ku : J.<D. Tsai : Y.<H. Choa : K.<H. Lue :


J.<N. Sheu (*)
Department of Pediatrics, Chung Shan Medical University Hospital,
No. 110, Section 1, Jianguo North Road, Taichung 402, Taiwan
e-mail: cshy098@csh.org.tw
T.<W. Hung
Department of Internal Medicine, Chung Shan Medical University
Hospital, Taichung, Taiwan
J.<D. Tsai : Y.<H. Choa : T.<W. Hung
Institute of Medicine, Chung Shan Medical University, Taichung,
Taiwan
M.<S. Ku : K.<H. Lue : J.<N. Sheu
School of Medicine, Chung Shan Medical University, Taichung,
Taiwan

Keywords Acute pyelonephritis . Renal ultrasonography .


Voiding cystourethrography . Renal scarring .
99m
Tc-dimercaptosuccinic acid scan . Vesicoureteral reflux

Urinary tract infection (UTI) is one of the most common


bacterial infections in febrile children 2 years [1]. The association between UTI and congenital abnormalities, such as
vesicoureteral reflux (VUR), may put children at a high risk
for acute pyelonephritis (APN) and subsequent renal scarring
(RS) [1, 2]. Although long-term complications of VUR and
infection-related renal damage are being questioned [3, 4], it is
believed that postpyelonephritic RS with recurrences, especially in the presence of high-grade VUR, may cause future
medical problems, such as hypertension and/or impaired kidney function. This has been the major driving force for the
comprehensive investigation and treatment of the first UTI
[58]. Therefore, choosing a diagnostic approach is based on

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identifying children who have VUR that may lead to additional infections and ongoing renal damage if not diagnosed
and managed appropriately after the first febrile UTI. Existing
guidelines propose different diagnostic algorithms that minimize invasive procedures while maintaining an acceptable
diagnostic ability to detect abnormalities [1, 911]. Renal
ultrasonography (US), voiding cystourethrography (VCUG),
and technetium-99m ( 99m Tc)-dimercaptosuccinic acid
(DMSA) scan are the core imaging methods. However, their
varying diagnostic ability, availability, invasiveness, and
procedure-related complications prevent any consensus on
the best approach. La Scola et al. [12] evaluated the diagnostic
ability of the five different guidelines for VUR and RS as well
as incurred cost and radiation exposure. The authors concluded there was no ideal diagnostic protocol after their first UTI.
We demonstrated that procalcitonin (PCT) was a good predictor of APN and high-grade VUR and that PCT 1.0 ng/ml
might be used as the first step of a diagnostic algorithm for
children after their first febrile UTI [13, 14]. We hypothesized
that the detection of the high-grade VUR and RS was important for children after their first UTI [58]. This study aimed to
examine the PCT protocol and compared it with four representative guidelines for its ability to detect VUR and RS [1,
911]. The cost and radiation burden of the different protocols
for children with their first febrile UTI were also evaluated.

Methods
This prospective cohort study evaluated children aged 2 years
who were admitted to an urban tertiary referral center with
their first febrile UTI. The hospitals Institutional Review
Board approved the study protocol, and the parents of all
participants provided informed consent. Diagnosis of a first
febrile UTI was based on the following:
1. Fever with body temperature 38 C
2. Presence of pyuria, defined as five or more white blood
cells per high-power field (WBC/hpf) and/or abnormal
dipstick urinalysis (positive nitrite or leukocyte esterase
tests)
3. Positive urine culture defined as any growth of a single
bacterium in urine from a suprapubic bladder aspiration,
or growth of a single microorganism 105 colony-forming
units (CFU)/ml collected from the midstream clean-void
urine specimen, or 5104 CFU/ml collected from a
transurethral catheterized specimen [1]
4. No previous history of UTI, kidney, bladder, or urogenital
disorder
Serum and urine indices for laboratory investigations, including PCT, C-reactive protein (CRP), WBC count, serum
creatinine (sCr), urinalysis, and urine and blood cultures were

Pediatr Nephrol (2014) 29:15671574

taken on admission and before initiation of antibiotic treatment. Rapid and quantitative measurements of PCT values
were done using enzyme-linked fluorescent assay in an
automated instrument (VIDAS PCT, B R A H M S
Diagnostica, Berlin, Germany) according to the manufacturers instructions. The detection limit was 0.05 ng/ml, and
PCT values 0.5 ng/ml were considered abnormal.
All children underwent complete imaging investigation,
including US, acute and late DMSA renal scan, and VCUG;
US was performed within the first 3 days of admission, and all
abnormal US findings considered to be related to VUR were
recorded. This included anteroposterior diameter of the renal
pelvis 5 mm and/or any grade of dilatation of calyces or
ureters; pelvic or ureteral wall thickening; absence of
corticomedullary differentiation; irregular renal outline and
signs of renal hypodysplasia (i.e., small kidney, thinned or
hyperechoic cortex); and duplicated renal collecting system
[13, 15]. DMSA scan was performed within the first 5 days of
admission to verify the presence of renal lesions. An abnormal
acute DMSA scan suggesting APN was defined as the presence of focal or diffuse areas of decreased uptake with preservation of the renal contour [16, 17]. If there was an abnormal
acute DMSA scan, a late DMSA scan was performed at least 6
months after the acute infection to evaluate the presence of late
RS. Previous studies showed that all children with normal
initial scan results had normal scans on follow-up [18]. Thus,
it was unnecessary to perform late DMSA studies on patients
with previously normal scans. RS was defined as the occurrence of focal or generalized areas of persistent diminished
uptake at the same locations as in the acute DMSA scan and/or
associated with loss of kidney contour or cortical thinning
with reduced volume [16, 17]. VCUG was performed 1
3 weeks after control of acute infection and graded IV
according to the International Reflux Study in Children [19].
Interpretations of the DMSA and VCUG were made by a
single experienced nuclear medicine physician and a single
experienced pediatric radiologist, both of whom were unaware of the patients clinical and laboratory findings and
who were blinded to the study.
Diagnostic guidelines
In the PCT protocol (PCT 2013) [13], a value 1.0 ng/ml was
selected as the first step of the diagnostic algorithm instead of
acute DMSA scan and VCUG for revealing APN and VUR
[13]. The four more recent (published after 2007), wellknown, representative guidelines in different areas, including
the American Academy of Pediatrics (AAP 2011) [1],
National Institute of Clinical Excellence (NICE 2007) [9],
top-down approach (TDA 2007) [10], and Italian Society of
Pediatric Nephrology (ISPN 2012) [11], were selected. Their
application on eligible children from this PCT cohort study
was retrospectively simulated (Table 1). Diagnostic guidelines

Pediatr Nephrol (2014) 29:15671574

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Table 1 Imaging recommendations in the five representative guidelines for a first febrile urinary tract infection (UTI) in children
Guidelines

US

Acute DMSA

VCUG

Late DMSA

AAP [1]
NICE [9]
<6 months
6 months
TDA [10]
ISPN [11]
PCT [13]

Yes

No

Yes, if abnormal US

No

Yes
If atypical UTIa
No
Yes
No

No
No
Yes
No
No

If abnormal US or atypical UTIa


If presence of risk factorsb
If abnormal acute DMSA
If abnormal US and/or presence of risk factorsc
If PCT 1.0 ng/ml

If atypical UTIa
If atypical UTIa
If abnormal acute DMSA
If abnormal US and/or presence of risk factorsc
If PCT 1.0 ng/ml

AAP American Academy of Pediatrics, NICE National Institute of Clinical Excellence, TDA top-down approach, ISPN Italian Society of Pediatric
Nephrology, PCT procalcitonin, UTI urinary tract infection, US renal ultrasonography, DMSA 99m Tc-dimercaptosuccinic acid, VCUG voiding
cystourethrography, VUR vesicoureteral reflux
a
Seriously ill, poor urine flow, abdominal or bladder mass, raised creatinine, septicemia, failure to respond to treatment with suitable antibiotics within
48 h, or infection with non-Escherichia coli organisms
b

Dilatation on US, poor urine flow, non-E. coli infection, or family history of VUR

Abnormal prenatal US, family history of VUR, septicemia, chronic kidney disease, age <6 months in a male infant, abnormal bladder emptying, no
clinical response to appropriate antibiotic treatment within 72 h, or non-E. coli infection

were applied for their ability to detect VUR and RS and to


evaluate total and individual costs and radiation burden. The
completed studies of children who underwent US, acute and
late DMSA scans, and VCUG during the protocol were used
as a reference to compare with the five different guidelines.

were performed using the SPSS for Windows (version


15.0; SPSS Inc., Chicago, IL, USA).

Costs, radiation exposure, and measurement outcomes

Patients and clinical characteristics

Costs incurred by the different protocols were calculated


based on price lists of the Taiwan National Health Insurance
Administration, as follows, in New Taiwan dollars (NTD):
DMSA renal scan $2,750; US $870; VCUG $1,090; PCT
$1,000). Reported radiation dose associated with the VCUG
procedure varied from 0.5 to 3.2 mSv [2]. DMSA renal scan
radiation dose was estimated to be 1 mSv regardless of the
childs age [2, 20]. For convenience, both imaging methods
were used as radiation burden of 1 mSv in this study. The
diagnostic ability for detecting VUR (grades IV and grades
IIIV) and RS after the first febrile UTI was examined according to each guideline. Costing and radiation dose of each
diagnostic protocol was then evaluated.

A total of 278 children 2 years with their first febrile UTI


who underwent complete diagnostic tests and follow-up were
enrolled. Demographic and clinical characteristics are
summarized in Table 2. Of the 278 children, 237
(85.3 %) were <1 year old, with a male-to-female ratio of
1.86:1. There were 41 (14.7 %) children aged 12 years, with a
male-to-female ratio of 0.86:1. All boys were uncircumcised,
as is customary in Taiwan. The most common causative microorganism was Escherichia coli, which was isolated in 238
children (85.6 %); 40 (14.4 %) children had other bacteria,
including Klebsiella, Proteus, Citrobacter, Pseudomonas, and
Enterococcus spp. Clinical and demographic data of infants <2 months were similar to those of the total population.
The effect of age on PCT values was analyzed, and no correlation was found (r=0.0120, p=0.848). There were no differences in PCT values between E. coli and non-E. coli groups (p=
0.357) or Gram-negative and Gram-positive groups (p=0.519).

Statistical analyses
Nonparametric data were assessed using the MannWhitney
U test; chi-square test was used to compare group proportions
with qualitative data. Diagnostic values of sensitivity, specificity, and positive (PPV) and negative (NPV) predictive
values, and positive (LR+) and negative (LR) likelihood
ratios were calculated. Multivariate analysis with stepwise
procedure was used to identify potential predictors of RS.
Results are expressed as odds ratio (OR), 95 % confidence interval (95 % CI), and p value. Statistical significance was set at p < 0.05. All statistical analyses

Results

Imaging findings
APN was found in 172 (61.9 %) children (105 boys, 61 %; 67
girls, 39 %). The remaining 106 (38.1 %) (68 boys, 64.2 %; 38
girls, 35.8 %) had lower UTI. Abnormal US findings associated with VUR were seen in 96 (34.5 %) children: various
grades of dilatation of the anteroposterior diameter and/or
dilation of calyces or ureters in 68 children, duplex kidney

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Pediatr Nephrol (2014) 29:15671574

Table 2 Clinical characteristics, procalcitonin (PCT) value, and imaging findings of the total population and infants <2 months
Variable

All children (n=278)

<2 months (n=27)

P value

Age, median (range), month


Gender, male/female
Aged <6 months
Escherichia coli//non
E. coli
PCT (1 ng/ml) (%)
Acute pyelonephritis (%)
Abnormal US (%)
VUR grades IV (%)
VUR grades IIIV (%)
Renal scarring (%)

5 (0.524)
173/105
119/58
238/40

1.5 (0.51.9)
17/10

0.940

23/4

0.952

163/278 (58.6)
172/278 (61.9)
96/278 (34.5)
101/278 (36.3)
73/278 (26.3)
75/278 (27.0)

16/27 (59.3)
18/27 (66.7)
14/27 (51.9)
12/27 (44.4)
10/27 (37.0)
8/27 (29.6)

0.950
0.777
0.114
0.532
0.330
0.945

VUR grades IV (%)


VUR grades IIIV (%)

59/101 (58.4)
53/73 (72.6)

8/12 (66.7)
7/10 (70.0)

0.759
1.000

US renal ultrasonography, VUR vesicoureteral reflux

in four, solitary kidney in three, and hypoplastic kidney in 21.


Of the 278 children, VUR (maximum degree of reflux given if
bilateral) was diagnosed in 101 (36.3 %), including 73
(26.3 %) with grades IIIV VUR. There was no difference
in VUR incidence between boys and girls (p = 0.549).
Children with APN had significantly higher VUR rates than
those with lower UTI (47.1 % vs. 18.9 %, p<0.001). The rate
of APN in children with VUR was significantly higher than in
children without VUR (80.2 % vs. 51.4 %, p<0.001). There
was also a significant association between APN and VUR
severity (50.0 % for grades III vs. 91.8 % for IIIV,
p<0.001).

detect RS. NICE had the highest specificity (86.2 %) and


ISPN the least (27.1 %) for detecting RS.
Association between RS and VUR
Of children with VUR, 58.4 % (59/101) had RS compared
with 22.5 % (16/177) without VUR (p<0.001). Among children with no or III VUR, 22.2 % (22/99) had RS compared
with 72.6 % (53/73) of those with IIIV VUR (p<0.001).
There was no difference in RS incidence between sexes (p=
0.392). Multivariate analysis confirmed that the incidence of
RS was significantly correlated with PCT values and presence
of VUR (Table 4). The risk significantly increased with grade.

Primary outcomes
Secondary outcomes
VUR grades IV and IIIV and late RS
Costs and radiation exposure
The diagnostic ability for detecting VUR grades IV and III
V and late RS among the five different guidelines is summarized in Table 3. TDA and PCT had the highest sensitivity and
NPV for detecting VUR grades IV (80.2 % and 81.1 %,
respectively, for TDA) and grades IIIV (94.5 % and 96.5 %,
respectively, for PCT). The LR of IIIV VUR was 0.10 for
the PCT protocol, which meant that children without IIIV
VUR were ten times more likely to have a PCT <1.0 ng/ml
compared with those with IIIV VUR. NICE had the least
sensitivity for IV (43.6 %) and IIIV (56.2 %) VUR; AAP
had the highest specificity for detecting IV and IIIV VUR
(77.4 % and 78.0 %, respectively); ISPN had the least specificity (25.4 % and 32.7 %, respectively).
Of 278 children, 75 (27.0 %) had RS; 59 of 75 (78.7 %)
had demonstrable VUR. Both TDA and PCT detected all RS
and had the highest sensitivity and NPV (100 % and 100 %,
respectively). AAP did not recommend a late DMSA scan to

The TDA protocol had the highest procedural costs and radiation dose, whereas AAP had the least among the five guidelines, with a 4.1-fold difference in payment and 6.4-fold
difference in radiation (Table 5).

Discussion
This study consecutively enrolled children 2 years with their
first febrile UTI. Male predominance during the first year of
life (circumcision is not a common procedure in Taiwan) was
characteristic of the study population, consistent with previous
reports [21, 22], except for La Scolas findings (64 % female
in their population) [12]. In the study reported here, 61.9 % of
children had acute abnormal DMSA scans, which is consistent
with reported values (5172 %) of previous publications [10,

Pediatr Nephrol (2014) 29:15671574

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Table 3 Diagnostic performances of the five different guidelines for predicting vesicoureteral reflux (VUR) grades IV (n=101) and IIIV (n=73) and
renal scarring (RS) (n=75) in children after first febrile urinary tract infection (UTI)
Parameter

AAP
IV

NICE
IIIV

RS

IV

TDA
IIIV

RS

ISPN

IV

IIIV

RS

IV

PCT
IIIV

RS

IV

IIIV

RS

Number

56/101

52/73

NA

44/101

41/73

24/75

81/101

67/73

75/75

63/101

57/73

47/75

77/101

69/73

75/75

Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
LR+
LR

55.4
77.4
58.3
75.3
2.45
0.58

71.2
78.0
54.2
88.5
3.23
0.37

NA
NA
NA
NA
NA
NA

43.6
74.6
49.4
69.8
1.72
0.76

56.2
76.6
46.1
83.1
2.40
0.57

32.0
86.2
46.2
77.4
2.32
0.79

80.2
48.6
47.1
81.1
1.56
0.41

91.8
48.8
39.0
94.3
1.79
0.17

100
52.2
43.6
100
2.09
0a

62.4
25.4
32.3
54.2
0.84
1.48

78.1
32.7
29.2
80.7
1.16
0.67

62.7
27.1
24.1
66.3
0.86
1.38

76.2
51.4
47.2
79.1
1.56
0.46

94.5
54.1
42.3
96.5
2.06
0.10a

100
56.7
46.0
100
2.31
0a

AAP American Academy of Pediatrics, NICE National Institute of Clinical Excellence, TDA top-down approach, ISPN Italian Society of Pediatric
Nephrology, PCT procalcitonin, VUR vesicoureteral reflux, RS renal scarring, UTI urinary tract infection, PPV positive predictive value, NPV negative
predictive value, LR+ positive likelihood ratio, LR negative likelihood ratio
a

Good diagnostic ability (LR 0.1)

16, 21, 23]. APN rate also significantly increased with the
presence and severity of VUR, similar to previous studies [8,
10, 23, 24]. When VUR was present, 8090 % of children
with febrile UTI had acute abnormal DMSA scans [3, 8, 25],
similar to findings presented here (80.2 %). Our results show
that 27.0 % of the entire population and 72.6 % of children
with IIIV VUR had RS, revealing a significant association
between RS and VUR grade, consistent with previous reports
[8, 23, 24, 26]. Our findings also show that VUR is a risk
factor for RS, particularly in grades IIIV VUR [68, 24, 27],
suggesting that VUR is a clinically significant condition
[24, 28].
A diagnostic test with the highest sensitivity is not necessarily the best in view of the uncertainty of the benefits of
detecting abnormalities (VUR and RS) in children with UTI.
Table 4 Risk factors for renal scarring: multivariate analysisa
Variables

Age (month)
12
>12
Gender
Boy
Girl
PCT
VUR
No
III
IIIV

Odds ratio

95 % confidence
interval

P value

1 (reference)
2.841

0.71911.228

0.137

1 (reference)
0.887
1.530

0.3192.464
1.2971.805

0.818
<0.001

1 (reference)
48.752
73.968

8.203289.752
18.761291.632

<0.001
<0.001

VUR vesicoureteral reflux, PCT procalcitonin


a

For multivariate analysis, a binary logistic regression model with stepwise procedure was used

On the other hand, if identifying abnormal test results does not


matter clinically, then the highest sensitivity is not necessarily
the best. Although the long-term clinical significance of VUR
and UTI-related RS in previously healthy kidneys remains
incompletely understood [29], reports show a significant correlation between reflux grade and RS frequency, suggesting that
VUR increases the risk of RS formation after UTI [68, 24, 27],
which may lead to late hypertension, proteinuria, and impaired
renal function [5, 30]. Early VUR and UTI-related RS detection
is therefore of key importance in the diagnostic assessment of
any infant and young child with a first febrile UTI. Although
the five different diagnostic protocols are designed in different
algorithms to evaluate children at the time of first febrile UTI,
they have the same goal of detecting any child who is at a high
risk for renal damage and also to reduce unnecessary imaging
following UTI. A more comprehensive protocol has a higher
sensitivity for detecting VUR and RS but is also costly and
incurs risks of exposing children to attendant radiation and
sedation. Thus, it is reasonable to design a less invasive algorithm by which to identify abnormalities and RS and to reduce
cost and radiation exposure in a selected population.
Previous studies show that PCT is a reliable marker for
differentiating APN from lower UTI in children [14, 3133].
In cases in which the PCT value in children is <1.0 ng/ml, the
possibility of APN and VUR grades IIIV is low [13]. Thus,
PCT 1.0 ng/ml has been selected as the first step in the
diagnostic algorithm for further imaging in the PCT protocol.
Our results show that the PCT protocol had the best diagnostic
performance for detecting VUR grades IIIV (sensitivity
94.5 %, LR 0.10) (Table 3). This may encourage pediatricians to decide not to recommend an acute DMSA scan and
VCUG if PCT value is <1.0 ng/ml.
The three remaining guidelines (AAP, NICE, and ISPN)
use US together with the presence of risk factors as the first
step of the algorithm for further imaging. These may increase the

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Pediatr Nephrol (2014) 29:15671574

Table 5 Imaging evaluations that incurred costs and radiation burden in terms of the different guidelines
Completed tests
Cost of each test, NTD
PCT (n)
0
US (n)
241,860 (278)
Acute DMSA (n)
764,500 (278)
VCUG (n)
303,020 (278)
Late DMSA (n)
473,000 (172)
Total costs
178,2380
Cost/patient
6,411
Radiation dose of each test, mSv
DMSA (acute + late)
450
VCUG
278
Total radiation dose
728
Radiation/patient
2.62

AAP

NICE

TDA

ISPN

PCT

0
241,860 (278)
0
104,640 (96)
0
346,500
1,246

0
177,480 (204)
0
97,010 (89)
143,000 (52)
417,490
1,502

0
0
764,500 (278)
187,480 (172)
473,000 (172)
1,424,980
5,126

0
241,860 (278)
0
212,550 (195)
536,250 (195)
990,660
3,564

278,000 (278)
0
0
177,670 (163)
448,250 (163)
903,920
3,252

0
96
96
0.35

52
89
141
0.51

450
172
622
2.24

195
195
390
1.40

163
163
326
1.17

AAP American Academic of Pediatrics, NICE National Institute of Clinical Excellence, TDA top-down approach, ISPN Italian Society of Pediatric
Nephrology, PCT procalcitonin, NTD New Taiwan dollar, US renal ultrasonography, VCUG voiding cystourethrogram, DMSA 99mTcdimercaptosuccinic acid

probability of detecting abnormalities but also increase further


examinations. The study we present here also shows that the
NICE guideline has the least sensitivity for detecting VUR
because further imaging is only performed in highly selected
children, consistent with findings of a study by Ristola et al.
[34]. That study evaluated the applicability of NICE guidelines
for imaging studies in children <3 years and demonstrated that
NICE may be applicable to clinical use only in boys <6 months.
Both TDA and PCT protocols had the best ability to
identify RS (sensitivity 100 %, NPV 100 %) on a late
DMSA scan. NICE and ISPN guidelines recommend a late
DMSA scan in selected children, resulting in modest sensitivity (62.7 %) for ISPN and least sensitivity (32.0 %) for NICE
in detecting RS. Evaluating the cost and radiation burden of
the five different guidelines, TDA had the highest cost and
radiation dose because they used acute DMSA scan results as
the first step of the algorithm; AAP did not recommend
DMSA scan, so it had the least cost and radiation exposure.
In the ISPN protocol, a male infant aged <6 months is an
indication for further imaging. In our study, the ratio of male
infants <6 months was 42.8 % of the study population
(Table 2), which is markedly different from the findings of La
Scola et al. [12], which reported a female predominance. If the
ISPN protocol is applied to our study population, the results
will have the least specificity for detecting VUR and RS among
the five guidelines. The ISPN protocol also carries higher costs
and radiation burden (Table 5). Our results are in contrast to
findings of La Scolas study [12], which showed that ISPN had
the highest specificity for detecting RS. Differences may be
attributed to the greater proportion of male infants aged
<6 months in our study. This may increase the number of
children for further investigation and could partially explain

the increased sensitivity rate for detecting VUR and RS, which
resulted in lower false-negative but higher false-positive rates in
the La Scola study. Findings from the small sample size in male
infants <6 months might not be enough to draw the conclusion
in the study. Thus, further prospective studies with larger cohorts are warranted to assess the issue.
Compared with decades ago, when all children with their
first febrile UTI required VCUG (nearly 70 % were unnecessary), current policy (all guidelines) reduces the number of
unnecessary VCUG. However, continuing efforts are necessary
regarding how to reduce unnecessary imaging for detecting
VUR and RS. AAP guidelines for arranging VCUG includes
abnormal US findings and febrile UTI recurrence to detect
VUR and/or to avoid unnecessary VCUG. Of the five sets of
guidelines, AAP has the highest specificity and PPV for detecting VUR. PCT and TDA guidelines have the highest ability to
detect VUR and RS; however, the PCT test and DMSA scans
are not performed in most children with UTI due to their limited
availability at most hospitals compared with the great number
of children with UTI. Thus, based on cost effectiveness, patient
safety (reduced need for sedation and radiation exposure), and
availability of imaging modalities, AAP guidelines have the
advantage in clinical practice, even though they are applicable
only to infants and to children 224 months with UTI. Thus,
PCT value in infants <2 months should be applied with caution.
This study has several strengths: Data were collected from
a single center, and it applied a consistent strategy for managing children with their first febrile UTI. It is also the first time
the PCT approach has was as a diagnostic algorithm and
compared with representative guidelines. Moreover, a multivariate regression analysis was conducted to examine independent predictors for late RS development after APN.

Pediatr Nephrol (2014) 29:15671574

Nonetheless, the study also has several limitations: First,


for convenience, the same radiation dose was used for both
DMSA and VCUG, and radiation exposure may be somewhat
different in different procedures and individuals. Second, as
the study was limited to hospitalized children at the time of the
first febrile UTI, findings may not be immediately generalized
or extrapolated to outpatients with UTI and to children with
afebrile or recurrent UTIs. Finally, the cost effectiveness derived from our study may be different than that in other heathcare markets. Study results must therefore be used with caution in other parts of the world.
In conclusion, there exists markedly varying diagnostic
abilities among different guidelines for detecting abnormalities and considering costs and radiation exposure in young
children and infants with their first febrile UTI. The PCTbased strategy is a good diagnostic protocol with which to
detect high-grade VUR and RS in that population. However,
higher costs and greater radiation burden remain shortcomings
of the PCT protocol. Pediatricians should make every effort to
reduce unnecessary imaging in such children. If based on
reducing costs and radiation burden, and considering the
availability of imaging modalities, clinical suggestions in the
AAP guidelines represent a considerable protocol.
Acknowledgments This study was supported by grants from the National Science Council, Taiwan (NSC93-2314-B-040-012) and the Chung
Shan Medical University Hospital, Taiwan (CSH-2012-C-010).

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