SUPPLEMENTARY TABLE 1.
Summary on number of patient, timing of VCUG and reported diagnostic accuracy parameters of the retrieved studies that
used first generation ultrasound contrast (Levovist) in the diagnostic accuracy assessment of contrast enhanced ultrasound.
Author (year) Number of patients, contrast application
and comparator test
Bosio (1998)a 58 children, 18 cases using Echovist and 40 Taking VCUG as standard (11 patients with 22
cases using Levovist. Only 38 cases with
contrast enhanced ultrasound was
performed followed by comparator of
VCUG and radionuclide studies
Mentzel (1999)b 46 children, all used Levovist, all compared Concordant findings in 78 ureteral unit (92.9%).
with VCUG, which was performed after
contrast enhanced ultrasound
Darge (1999)c 188 children, all used Levovist, all
compared with VCUG, which was
performed after contrast enhanced
ultrasound
Ascenti (2000)d 22 children, all used Levovist with color
doppler. All had VCUG within 5 days from
contrast enhanced ultrasound
Berrocal Frutos 169 children, all used Levovist, all
e
(2000) compared with VCUG, which was
performed after contrast enhanced
ultrasound
Farina (2000)f 18 children, all used Levovist with color
doppler, all compared with VCUG, which
was performed after contrast enhanced
ultrasound
Valentini 74 children, all used Levovist with color
(2000)g doppler, all compared with VCUG, which
Diagnostic accuracy parameters reported remarks
“Levovist proved to be more
ureteral unit): sensitivity 100%; specificity 86%; In durable in solution than Echovist.”
the remaining 27 cases, contrast enhanced
ultrasound detected 32 episodes of VUR in 24
patients, while indirect radionuclide cystography
demonstrated 20 episodes of VUR in 17 patients.
Contrast manufacturer Schering,
VCUG as standard reference, sensitivity 91.7%, Berlin, Germany,
specificity 93.1%, accuracy 92.9%. positive helped with preparation of
predictive value 68.8% and negative predictive manuscript.
value 98.5%
Concordant findings in 208 ureteral units (92%). “The findings at 24-
“Using VCUG as the reference method, voiding hour follow-up was negative for
US with echo enhancement had a sensitivity of complications
100% and a specificity of 97%.” related to intravesical Levovist
administration”
“Medium to severe VUR (grades III–V) confirmed “No adverse events definitely
by radiological features was seen with 100% related to the intravesical
accuracy in 9/9. Mild VUR (grades I–II) was administration
detected at colour-Doppler contrast enhanced of Levovist were observed.”
ultrasound in only 4/11 subjects, reflecting an
extremely low sensitivity (36%).”
“When VCUG was used as the reference method, Article in Spanish
cystosonography had a sensitivity of 90.5% and a
specificity of 91.4%.”
“The VCUG confirmed the results in 14 patients “The superimposability of the data
(77.8%). There was no correspondence obtained with voiding color
between the two examinations in four cases Doppler US and VCUG would seem
(22.2%) (three false positive, one false negative).” to confirm the importance of this
new ultrasonographic technique in
the diagnosis and staging of VUR.”
“The agreement between contrast enhanced The diagnostic accuracy of contrast
ultrasound and VCUG in predicting VUR was 90%. enhanced color doppler study was
Using VCUG as standards in comparing significantly higher than that of
 was performed after contrast enhanced
ultrasound
Berrocal (2001)h 216 children, all used Levovist, all
compared with VCUG, which was
performed after contrast enhanced
ultrasound
CE-VUS and VCUG, the sensitivity of CE-VUS in contrast enhanced ultrasound
diagnosing VUR was 81% (34 of 42 units; 95% CI, study (96% versus 90% of cases
75–89%), and the specificity was 95% (72 of 76 correctly classified).
units; 95% CI, 91–99%); the overall diagnostic
accuracy of contrast enhanced ultrasound was
90% (106 of 118 units; 95% CI, 84–95%); the
positive and negative predictive values were 89%
(34 of 38 units; 95% CI, 84–95%) and 90% (72 of
80 units; 95% CI, 85–95%), respectively.” “The
sensitivity of contrast enhanced with color
doppler in diagnosing VUR was 100% (42 of 42
units; 95% CI, 94–100%), and the specificity was
93% (71 of 76 units; 95% CI, 89–98%). The overall
diagnostic accuracy was 96% (113 of 118 units;
95% CI, 92–99%). The positive and negative
predictive values were 89% (42 of 47; 95% CI, 84–
95%) and 100% (71 of 71; 95% CI, 94–100%),
respectively. The agreement between the CE-
CDVUS and VCUG diagnoses was 96%”
“Concordance of the two methods for the “Cystosonography with SH U 508A
identification of VUR was 0.769+0.035. The appears comparable to VCUG in
comparison of cystosonography the depiction of VUR”
with VCUG showed that both techniques
were concordant for the presence or absence
of VUR and for the grade of VUR in
83.7% of renal units. There was concordance
in the detection of VUR but not in
the grade of VUR in 3.8% of the units.
Cystosonography tended to depict a
higher grade of VUR than did VCUG
when both tests demonstrated VUR. In
fact, in all of the units with different
grades of VUR detected with each technique
(when both tests showed VUR), a
higher grade was depicted at cystosonography
than at VCUG. Grades 2 and 3
VUR tended to be underestimated at
VCUG: 28 of the 29 units with a positive
cystosonogram and a negative VCUG image
were depicted with grades 2 and 3

Radmayr (2002) i
104 children, all used Levovist, all
compared with VCUG, which was
performed after contrast enhanced
ultrasound
Mendez (2002)j 442 patients, all used Levovist, only initial
70 patients considered for comparator
VCUG
McEwing 97 neonates, all used Levovist, all
(2002)k compared with VCUG, which was
performed after contrast enhanced
ultrasound
Nakamura 33 children, all used Levovist
(2002)l simulataneously performed with
radiocontrast and VCUG.
Mentzel (2002)m 118 children, all used Levovist, all
compared with VCUG, which was
performed after contrast enhanced
ultrasound
VUR at cystosonography
“Using voiding cystourethrography as the
reference method revealed a specificity,
sensitivity and accuracy of the contrast echo
enhanced reflux sonography of 96%. The
correlation coefficient of 0.9 was highly
significant”
“Of the 70 initial cases in which they were
Both contrast enhanced ultrasound and VCUG
were both performed, appreciated
of sensitivity of 100% with a specificity of 84%.
The negative predictive value (NPV) was 100%,
while the positive predictive value
(PPV) indicates 84%.
“The findings were concordant in 181 kidneys
(94.2%). Taking VCUG as gold standard, contrast
enhanced ultrasound had a sensitivity of 64%
(95% CI 35–87%), a specificity of 100% (95–
100%), a positive predictive value
of 100% (66–100%), and a negative predictive
value of 94% (87–98%)”
“If the assumption of VUR detected on either
method to represent true positive and no reflux
on both to represent true negative, sensitivity
and accuracy for contrast enhanced ultrasound
were 86% and 97%, while VCUG have 79% and
95% respectively.”
“Concordant findings were obtained in 210 of
224 ureterorenal units (93.7%). Reflux was
excluded by both methods in 174 units (77.7%).
With the VCUG as the reference, the sensitivity of
VUS was 90%, the specificity 94.6%, the positive
predictive value 78.3%, and the negative
predictive value 97.8%. The accuracy was 93.7%.”
“demonstrate that the safety and
accuracy of the diagnosis of VUR
by means of contrast-enhanced
ultrasound is statistically
comparable to those of standard
radiologic VCUG.”
Spanish article
“The role of echo-enhanced
sonography is limited at present in
our neonatal population as a
screening examination. Its ability to
detect cases of high-grade reflux
may make it an attractive
alternative in follow-up of known
cases of VUR, and may help to
reduce radiation exposure in this
group.”
“contrast enhanced ultrasound and
VCUG were performed
simultaneously, preliminary results
suggest the two techniques
demonstrate similar sensitivities in
detection of VUR”
Darge (2002)n 186 children, all used Levovist, all
compared with VCUG, which was
performed same session as contrast
enhanced ultrasound
Piaggio (2003)o 158 children, all used Levovist with color
doppler, all compared VCUG, which was
performed same session as contrast
enhanced ultrasound
Riccabona 30 children, all used Levovist with color-
(2003)p doppler with burst technology setting of
ultrasound, all compared VCUG, which was
performed same session as contrast
enhanced ultrasound
Uhl (2003)q 24 children, all used Levovist
simultaneously performed with
radiocontrast and VCUG.
Nakamura 56 children, all used Levovist
(2003)r simultaneously performed with
radiocontrast and VCUG
“Total of 95 KUUs were available for analysis. The Basis for grading of VUR on
analysis of VUS reflux grades with respect to contrast enhanced ultrasound was
VCUG grades revealed that in 59/95 (62%) KUUs, configured in this study
the grades were the same in both examinations.
In 10/95 (11%) and 26/95 (27%) KUUs, the reflux
was graded lower or higher, respectively, in the
VUS than in the VCUG. A significant disparity was
found in the number of refluxive KUUs with
grades I and II refluxes in the two imaging
modalities (P>0.01). In 70% of KUUs diagnosed as
having grade I reflux in the VCUG, grade 2 and
higher was actually diagnosed in the VUS.”
In 238 ureteral units there was an agreement “Contrast enhanced ultrasound can
between the two techniques (78%), whereas in be an alternative to VCUG under
67 cases (22%) there was no agreement. the following conditions (excluding
Considering only the VUR-positive cases, the males at first diagnosis, when
percentage with no agreement rises to 61.5%. VCUG is essential for visualization
of urethral morphology, due to the
incidence of malformations, valves,
close or open syringoceles,
stenosis, etc.)”
“In relation to all 24 refluxes detected by either “demonstrate that the
VCUG or contrast enhanced ultrasound, statistical additional burst-CS using high
results were Conventional non-color doppler output energy
contrast enhanced ultrasound including all improves US VUR detection and
equivocal cases had an accuracy of 84.8%, a thus contributes
sensitivity of 70.8%, a specificity of 92.9%, and a to more reliable ee-CS results.”
negative predictive value of 84.7%. c) Burst with
color doppler-contrast enhanced ultrasound had
an accuracy of 95.5%, a sensitivity of 91.7%, a
specificity of 97.6%, and a negative predictive
value of 93.2%.
“Taking the VCUG as the reference standard, VUS
had 84% sensitivity, 100% specificity, 100% and
90% positive and negative predictive values,
respectively.”
“Assuming that VUR detected by either method Update study of Nakamura 2002.
was representative of a true-positive, and no “Levovist concentrations in bladders
reflux by either method was representative of a ranged from 1.8% to 23%, with older
children tending to demonstrate

Xhepa (2004)s 34 children, all used Levovist, 22 cases with
VCUG on the same day or 2-5 days before
or after contrast enhanced ultrasound
Vassiou (2004) t 76 children, all used Levovist, all used
Levovist, all compared with VCUG, which
was performed same session as contrast
enhanced ultrasound
Galia (2004)u 122 children, all used Levovist with color
doppler ultrasound, all compared with
VCUG, which was performed same session
as contrast enhanced ultrasound
true-negative, sensitivity and accuracy of both
VUS and VCUG for detection of VUR would be
86% and 96%,respectively. No complications of
simultaneous intra-vesical application of the two
contrast agents were observed.” Patients under
24-mo of age displayed a better Sensitivity, of
94% for contrast enhanced ultrasound.”
“The comparative study demonstrated a
concordance in the diagnosis of reflux in 30 of 45
(66.6%) ureteral units”
“Regarding to the presence of VUR, the findings
obtained by both methods were concordant
in 17 ureteral units. Taking VCUG as the
reference standard, the sensitivity of contrast
enhanced ultrasound was 96 %, the specificity
was 94.8 %, the positive predictive value 77.4 %
and the negative predictive value 99.2 %.”
“In 231 (94.2%) of the 244 ureterorenal units,
there was concordance between the two
methods. The echoenhancing agent was well
tolerated by all patients.” “using VCUG as the
reference method, voiding color Doppler US
with Levovist had an overall sensitivity of 100%,
an overall specificity of 91%, a positive predictive
value of 86.7%, a negative predictive value of
100%, and an accuracy of 94.6%.”
increased bladder capacity and lower
concentration. All VUS false-negative
units displayed Levovist bladder
concentrations of less than 5%.”
“contrast enhanced ultrasound has
good reproducibility, but the
quality of the examination depends
on the operator’s experience. With
rigorous training and strong
motivation of dedicated
professionals, dynamic
urethrosonography without
contrast medium and echo-
enhanced CUS could be of great
benefit for the identification in
children with potentially dangerous
pathologies (such as severe reflux
and/or urethral obstruction),
particularly in developing
countries”
“CES is an accurate and reliable
imaging modality for the detection
of VUR, although it cannot replace
VCUG in some cases. In addition,
CES can be recommended in the
follow-up of VUR, reducing the
number of radiographic
investigations.”
“Proposed the first diagnostic
technique to detect and stage
vesicoureteral reflux may be
voiding color Doppler US with echo
enhancement. If reflux is detected,
standard VCUG would be necessary
in some cases to assess the
urethral anatomy.”
Darge (2005)v 55 children, all used Levovist with
Harmonic imaging, all compared with
VCUG,which was performed same session
as contrast enhanced ultrasound
Castagnetti 56 children, all used Levovist with power
(2006)w doppler and color doppler, All compared
with VCUG, which was performed same
session as contrast enhanced ultrasound
Giordano 610 children, 563 used Levovist, 47 used
(2007)x Sonovue and used power doppler scan,
only 60 of 610 patient underwent VCUG
when contrast enhanced ultrasound was
non-diagnostic
Galloy (2008)y 130 children, all used Levovist, All
compared with VCUG, which was
performed same session as contrast
enhanced ultrasound
Piscitelli (2008)z 157 children, all used Levovist, 118 had
comparative VCUG, 39 had direct
radionuclide voiding cystogram after
contrast enhanced ultrasound
“There was a 91.2% concordance rate between
contrast enhanced ultrasound and VCUG. Taking
VCUG as the reference method, VUS had the
following diagnostic results: 86.4% sensitivity,
92.4% specificity, positive and negative predictive
values of 73.1 and 96.6%, respectively.”
“Vesicoureteric reflux was detected by both
techniques in 31 UUs; grade was the same in 23
(74%) UUs. “Accordingly, sensitivity of PD-VUS
compared with VCUG considering UUs was 94%,
specificity 92.4%, PPV 83.7%, NPV 97.3%, and
diagnostic accuracy 92.8%”.” “Accordingly,
considering the number of patients, sensitivity of
VUS was 100%, specificity 88%, PPV 88%, NPV
100%, and accuracy 94.6%.”
“Diagnostic disagreement was recorded in only 3
of 60 children examined with VCUG (5%; two
false-negative, one false-positive).” the diagnostic
agreement in the 60 subjects examined with both
methods, VUS and VCUG, is 96%. “
“The results of VUS compared to VCUG as a
reference method for the detection of reflux,
sensitivity, specificity, PPV and NPV values of
62.7%, 83.4%, 50.0% and 89.4%, respectively.”
“In the identification of 4°–5° grade reflux, the
sensitivity of VUS reached 100% with VCUG as
standard.” When VUS and DRVC were compared,
there was concordance between the results
for the detection of VUR (100% sensitivity)
First application of harmonic
ultrasound setting in Levovist dose
halfed. “Even when the dose of US
contrast medium is halved, the
diagnostic efficacy of harmonic
VUS is comparable to VCUG.
Consequently, we recommend an
US contrast medium dose of 5% of
the bladder filling volume for the
diagnosis of VUR using contrast-
enhanced harmonic VUS.”
Bias of patient selection to undergo
VCUG is present, not all patient
was requested with VCUG, a
diagnostic flow chart was
implemented for the study.
In children with reflux, grading was
generally higher with VUS than
with VCUG, and the corresponding
weighted k values indicated
moderate concordance between
the two techniques for each
reviewer (0.42 and 0.44,
respectively) and after consensus
(0.45).
“data suggest that VUS represents
a valid alternative in the diagnosis
and stadiation of refluxes in girls,
the follow-up of VUR previously
diagnosed, the screening of groups
 at high risk (siblings of patients
with VUR and patients with
transplants), reserving the use of
VCUG as the first method
in the infant boys, in whom the
morphological study of the
urethra is necessary for the
evaluation of urethral and/or
bladder imaging.”

Citations:

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SUPPLEMENTARY TABLE 2. Summary on number of patient, timing of VCUG and reported diagnostic accuracy parameters of the retrieved studies that used
second generation ultrasound contrast (Sonovue) in the diagnostic accuracy assessment of contrast enhanced ultrasound.
Author (year) Number of patients, contrast application
and comparator test
Ascenti (2004) I 80 children, all used Sonovue with contrast
specific mode, VCUG was performed on
same session in 57 patients, while 27
patients had VCUG within 3 days from
contrast enhanced ultrasound
Papadopoulou 228 children, all used Sonovue, two cycle
(2009)II contrast enhanced ultrasound with
contrast specific setting, and all compared
with VCUG, which was performed on the
same secession with the contrast enhanced
ultrasound
Kis (2010)III 183 children, all used Sonovue with
harmonic imaging setting, all compared
with VCUG, which was performed in the
same session with contrast enhanced
ultrasound
Duran (2012)IV 295 children, all used Sonovue with
contrast specific imaging, select cases with
urethral pathology underwent VCUG for
confirmation.” Three criteria were used for
quality assessment of the bladder image:
(1) progressive incorporation
of contrast material in the bladder, (2)
homogeneous bladder-filling to maximum
capacity, and (3) visualisation of the
posterior bladder wall.”
Kljucevsek 66 children , all used Sonovue with
(2012)V contrast specific software. All compared
with VCUG, which was performed
immediately after contrast enhanced
ultrasound.
Diagnostic accuracy parameters reported
“With respect to the VUS, sensitivity and negative
predictive value of VCUG were inferior (94 and
97% respectively). Specificity and positive
predictive value were 100% both for VCUG and
VUS.”
“Concordance in findings regarding the presence
or absence of VUR was found in 359/463 (77.5%)
ureteral unit. Considering VCUG as the reference
standard, the sensitivity of VUS was 80%.
Considering as true-positive all refluxing KUUs
shown with either method, the sensitivity
of VUS and VCUG was 92% and 64%,
respectively”
“In 315 cases, the KUU results were the same by
both methods (86.3%)”
Criterion 1 was fulfilled in 305 (99.3%), criterion 2
in 304 (99%) and criterion 3 in 304 (99%) studies.
In children who underwent VUS with both
contrast agents, the concordance between the
two techniques was moderate for findings in the
bladder and perfect for findings in the male
urethra
Considering VCUG as the reference method to
detect VUR in children younger than one year,
the sensitivity of echo-enhanced VUS, regardless
of the grade of VUR, was 100% and the specificity
77.5 %. Normal renal US an unreliable predictor
remarks
First study to use second
generation ultrasound contrast
(Sonovue) and application of
harmonic setting of ultrasound.
No adverse events related to
administration of the second-
generation contrast agent up to
24h after the examination were
recorded.
“findings suggest that contrast-
enhanced harmonic VUS using a
second-generation contrast agent
is superior to VCUG in the
detection and grading of VUR, and
it should be the method of choice
for this clinical indication.”
“No adverse effects related to the
UCA were observed during the
examination or reported during the
48 h after the examination”
No adverse events related to the
intravesical administration
of contrast agent occurred as was
reported by nephrologists
who sent the children to voiding
cystography

Deng (2013)VI 36 children, all used Sonovue with
harmonic ultrasound setting, all compared
with VCUG performed same session with
contrast enhanced ultrasound
Wozniak 80 children for assessment of accuracy, all
(2013)VII used Sonovue with B-mode, color doppler
and contrast specific mode. All compared
with VCUG which was performed in the
same session as contrast enhanced
ultrasound
Wong (2014)VIII 31 children, all used Sonovue with contrast
specific setting, all compared with VCUG
performed same session with contrast
enhanced ultrasound
Babu (2015)IX 2 children, both used Sonovue and contrast
specific mode, compared with VCUG
Faizah (2015)X 27 children, all used Sonovue and contrast
specific mode, all compared with VCUG,
which was performed immediately after
contrast enhanced ultrasound
Piskunowicz 83 children, all used Sonovue, based on
(2016)XI images, contrast specific mode was used.
All had VCUG performed simultaneous
with contrast enhanced ultrasound
of VUR (negative predictive value 0.71).
Ureteropelvicalyceal dilatation is a more
reliable predictor of VUR (positive predictive
value 0.375), yet not reliable enough to
substitute various cystographyes in detecting
VUR
The concordance of two modalities yielded the
same results for 65 ureteral unit (90.3%)
The concordance between the two methods, i.e.
VCUG and ce-VUS, was 86.95%. With VCUG as a
reference method, the sensitivity of ce-VUS was
84.51%, specifi city – 90.99%, PPV – 85.71%
and NPV – 90.17%.
Taking the presence and absence of VUR rated by
both modalities, there was a high concordance at
85.5 % (53/62). Taking VCUG as the reference
method, the sensitivity of contrast enhanced
ultrasound was 100 % and specificity was 84 %
Both studies revealed similar findings.
The sensitivity and specificity of contrast
enhanced ultrasound in the detection of VUR was
80% and 98%, respectively. The overall accuracy
was 95%. Contrast enhanced ultrasound had a
positive predictive value of 89%, and a negative
predictive value of 96%. Contrast enhanced
ultrasound and VCUG findings were in agreement
with VUR grades in six of eight cases (75%)
The sensitivity of voiding cystourethrography and
contrast enhanced voiding urosonography
were comparable, amounting to 88%, however,
neither reached 100% for the entire studied
population. The negative predictive value of
voiding urosonography and voiding
Chinese article
Study had a second phase which
used 3D and 4D imaging and
assessed the diagnostic capability
and fesibility
No immediate or delayed
complications were encountered in
any of our cases. No incidents
related to contrast allergy,
infection or catheterization were
identified
No adverse effects related to the
ultrasound contrast observed
during the examination or reported
by the parents during the 48 hours
after the examination.
final diagnosis (FD)
was established as the reference
method. In particular,
the patient was considered as
having vesicoureteral reflux
when the presence of VUR was
detected by either of

Wozniack 69 children, all used Sonovue with B-mode,
(2016)XII color doppler, contrast specific image
mode with 3D and 4D realtime
reconstruction, all compared with VCUG
Fernandez- 40 children, all used Sonovue in contrast
Ibieta (2016)XIII specific setting, all compared with VCUG,
which was performed in the same morning
session
Colleran 4 children, all used Sonovue, based on
(2016)XIV figure images, contrast specific setting
used. All have a comparison with VCUG
cystourethrography was 97%, and there was no
difference between both methods
2DUS and 3DUS/4DUS urosonography diagnosed
10 more refluxes (7.25%) than cystourethrogra-
phy and in 3 refluxes (2.17%) detected a higher
grade. In 9 refluxes (6.52%) 3DUS/4DUS
urosonography andcystourethrography
diagnosed a higher grade than 2DUS. There was a
statistically significant difference between
cystourethrography and 3DUS/4DUS
urosonography when the number of detected
refluxes and differences in grading were
compared.
Concordance of both tests were = 0.73 (95% CI:
0.48-0.96), considered «Good concordance
index».
Intra-renal reflux (IRR) being depicted.
The ability of contrast-enhanced voiding
urosonography to show IRR when it occurs in
conjunction with VUR compares favorably to that
of fluoroscopic VCUG.
the compared methods (ce-VUS or
VCUG).
4DUS enabled a better visualization
of reflux than 3DUS.
Spanish article “No adverse effects
documented”
Cases of VUR accompanied by IRR
are generally considered
to be at the more severe end of the
clinical spectrum. Depicting
IRR at contrast-enhanced voiding
urosonography using a second
generation sonographic contrast
agent has not been reported
previously.

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