Diagnostic accuracy of contrast-enhanced voiding urosonogram using second-generation contrast with harmonic imaging (CEVUS-HI) study for assessment of vesicoureteral reflux in children: a meta-analysis

  • Michael E. ChuaEmail author
  • Jonathan S. Mendoza
  • Jessica M. Ming
  • Jun S. Dy
  • Odina Gomez
Original Article



To assess the diagnostic accuracy and safety of contrast-enhanced voiding urosonogram using second-generation contrast with harmonic imaging (CEVUS-HI) in detecting vesicoureteral reflux (VUR) among children.


A systematic literature search was performed in March 2018. Relevant comparative studies from Medline, EMBASE, World of Science, Scopus, CENTRAL, WHO trial registry and were identified and appraised using QUADAS-2. Diagnostic accuracy parameters were determined using VCUG as the reference standard. Adverse effects related to ultrasound contrast were summarized. The heterogeneity and inter-study variability were determined. After appropriate subgroup diagnostic accuracy parameters were investigated, summarizing receiver operator characteristics was constructed using the bivariate model meta-regression to determine the area under the curve (AUC).


A total of 12 studies with low–high risk of bias, including 1917 ureteral units from 953 patients were assessed for this meta-analysis. The included studies reported no serious adverse events associated with the ultrasound contrast. The pooled diagnostic accuracy parameters of CEVUS-HI in detecting VUR amongst children were: sensitivity 90.43 (95% CI 90.36–90.50), specificity 92.82 (95% CI 92.76–92.87), the calculated (+) likelihood-ratio 12.59 (95% CI 12.49–12.68), (−) likelihood-ratio of 0.103 (95% CI 0.102–0.104) and extrapolated pooled diagnostic odds-ratio was 122.12 (95% CI 120.75–123.49). Heterogeneity with interstudy variability was noted (p < 0.0001, I-squared > 70%). The AUC was determined to be 0.965 for VUR detection.


The pooled diagnostic accuracy parameters from low–moderate quality of evidence have illustrated that the CEVUS-HI study has an excellent safety profile and acceptable diagnostic accuracy. It may be considered as an alternative diagnostic modality for assessment of VUR among children.


Contrast-enhanced voiding urosonogram Diagnostic accuracy Vesicoureteral reflux Voiding cystourethrogram 


Author contributions

MEC: Protocol/project development, data collection or management, data analysis, manuscript writing/editing. JSM: Protocol/project development, data collection or management, data analysis, manuscript writing/editing. JMM: Data collection, manuscript editing/revision. JSD: Data analysis, manuscript writing/editing. OG: Protocol/project development, data collection or management, data analysis.



Compliance with ethical standards

Conflict of interest

All authors have nothing to disclose.

Ethics approval

The study was approved and registered in our institutional research board as exempt for review.

Supplementary material

345_2018_2587_MOESM1_ESM.doc (32 kb)
Supplementary material 1 (DOC 31 kb)
345_2018_2587_MOESM2_ESM.docx (2.9 mb)
Supplementary material 2 (DOCX 3000 kb)


  1. 1.
    Tekgül S, Dogan HS, Kocvara R, Nijman JM, Radmayr C, Stein R, Silay MS, Undre S, Quaedackers J (2018) EAU-ESPU-pediatric urology guidelines. European Association of Urology–non-oncology guidelines. 2018. Accessed 13 Mar 2018
  2. 2.
    Peters CA, Skoog SJ, Arant BS Jr, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M (2010) Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol 184(3):1134–1144. CrossRefPubMedGoogle Scholar
  3. 3.
    Duran C, Beltrán VP, González A, Gómez C, Riego JD (2017) Contrast-enhanced voiding urosonography for vesicoureteral reflux diagnosis in children. Radiographics. 37(6):1854–1869. CrossRefPubMedGoogle Scholar
  4. 4.
    Darge K (2008) Voiding urosonography with US contrast agents for the diagnosis of vesicoureteric reflux in children. II. Comparison with radiological examinations. Pediatr Radiol. 38(1):54–63CrossRefGoogle Scholar
  5. 5.
    Chua ME, Kim JK, Mendoza JS, Fernandez N, Ming JM, Marson A, Lorenzo AJ, Lopes RI, Takahashi (2018) The evaluation of vesicoureteral reflux among children using contrast-enhanced ultrasound: a literature review. J Pediatr Urol (In-Press). CrossRefGoogle Scholar
  6. 6.
    Novljan G, Levart TK, Kljucevsek D, Kenig A, Kenda RB (2010) Ultrasound detection of vesicoureteral reflux in children. J Urol. 184(1):319–324. (epub 2010 May 20) CrossRefPubMedGoogle Scholar
  7. 7.
    Macaskill P, Gatsonis C, Deeks JJ, Harbord RM, Takwoingi Y (2010) Chapter 10: Analysing and presenting results. In: Deeks JJ, Bossuyt PM, Gatsonis C (eds) Cochrane handbook for systematic reviews of diagnostic test accuracy version 1.0. The Cochrane Collaboration. Accessed May 2018
  8. 8.
    McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM, the PRISMA-DTA Group, Clifford T, Cohen JF, Deeks JJ, Gatsonis C, Hooft L, Hunt HA, Hyde CJ, Korevaar DA, Leeflang MMG, Macaskill P, Reitsma JB, Rodin R, Rutjes AWS, Salameh JP, Stevens A, Takwoingi Y, Tonelli M, Weeks L, Whiting P, Willis BH (2018) Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the PRISMA-DTA statement. JAMA. 319(4):388–396. CrossRefPubMedGoogle Scholar
  9. 9.
    Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM, QUADAS-2 Group (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 155(8):529–536. CrossRefPubMedGoogle Scholar
  10. 10.
    Review Manager (RevMan) (computer program) (2014) Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, CopenhagenGoogle Scholar
  11. 11.
    Zamora J, Abraira V, Muriel A, Khan KS, Coomarasamy A (2006) Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol 6:31CrossRefGoogle Scholar
  12. 12.
    Partlett C, Takwoingi Y (2016) Meta-analysis of test accuracy studies in R: a summary of user-written programs and step-by-step guide to using glmer. Version 1.0. August 2016. Available from: Accessed May 2018
  13. 13.
    Debray T, de Jong V (2018) Metamisc: diagnostic and prognostic meta-analysis. R package version 0.1.8. Accessed May 2018
  14. 14.
    Ascenti G, Zimbaro G, Mazziotti S, Chimenz R, Fede C, Visalli C, Scribano E (2004) Harmonic US imaging of vesicoureteric reflux in children: usefulness of a second generation US contrast agent. Pediatr Radiol 34(6):481–487 (epub 2004 Apr 24) CrossRefGoogle Scholar
  15. 15.
    Papadopoulou F, Anthopoulou A, Siomou E, Efremidis S, Tsamboulas C, Darge K (2009) Harmonic voiding urosonography with a second-generation contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol 39(3):239–244. (epub 2008 Dec 19) CrossRefPubMedGoogle Scholar
  16. 16.
    Kis E, Nyitrai A, Várkonyi I, Máttyus I, Cseprekál O, Reusz G, Szabó A (2010) Voiding urosonography with second-generation contrast agent versus voiding cystourethrography. Pediatr Nephrol 25(11):2289–2293. (epub 2010 Aug 5) CrossRefPubMedGoogle Scholar
  17. 17.
    Ključevšek D, Battelino N, Tomažič M, Kersnik Levart T (2012) A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. Acta Paediatr 101(5):e235–e239. (Epub 2012 Jan 27 PubMed PMID: 22211993) CrossRefPubMedGoogle Scholar
  18. 18.
    Deng J, Zhou L, Zeng S, Zhang C, Zeng G, Wang J, Chen Q (2013) Voiding urosonography with SonoVue and fluoroscopic voiding cystourethrography in evaluation of vesicoureteral reflux: a comparative study. Nan Fang Yi Ke Da Xue Xue Bao. 33(10):1467–1470 (Chinese) PubMedGoogle Scholar
  19. 19.
    Woźniak MM, Pawelec A, Wieczorek AP, Zajączkowska MM, Borzęcka H, Nachulewicz P (2013) 2D/3D/4D contrast-enhanced voiding urosonography in the diagnosis and monitoring of treatment of vesicoureteral reflux in children—can it replace voiding cystourethrography? J Ultrason 13(55):394–407. (epub 2013 Dec 30)
  20. 20.
    Wong LS, Tse KS, Fan TW, Kwok KY, Tsang TK, Fung HS, Chan W, Lee KW, Leung MW, Chao NS, Tang KW, Chan SC (2014) Voiding urosonography with second-generation ultrasound contrast versus micturating cystourethrography in the diagnosis of vesicoureteric reflux. Eur J Pediatr 173(8):1095–1101CrossRefGoogle Scholar
  21. 21.
    Faizah MZ, Hamzaini AH, Kanaheswari Y, Dayang AAA, Zulfiqar MA (2015) Contrast enhanced voiding urosonography (ce-VUS) as a radiation-free technique in the diagnosis of vesicoureteric reflux: our early experience. Med J Malaysia 70(5):269–272PubMedGoogle Scholar
  22. 22.
    Fernández-Ibieta M, Parrondo-Muiños C, Fernández-Masaguer LC, Hernández-Anselmi E, Marijuán-Sauquillo V, Ramírez-Piqueras M, Argumosa-Salazar Y, Moratalla-Jareño T, Fernández-Córdoba MS (2016) Voiding urosonography with second-generation contrast as the main tool for examining the upper and lower urinary tract in children. Pilot Study. Actas Urol Esp. 40(3):183–189. (epub 2015 Dec 31) CrossRefPubMedGoogle Scholar
  23. 23.
    Woźniak MM, Wieczorek AP, Pawelec A, Brodzisz A, Zajączkowska MM, Borzęcka H, Nachulewicz P (2016) Two-dimensional (2D), three-dimensional static (3D) and real-time (4D) contrast enhanced voiding urosonography (ceVUS) versus voiding cystourethrography (VCUG) in children with vesicoureteral reflux. Eur J Radiol 85(6):1238–1245. (epub 2015 Nov 5) CrossRefPubMedGoogle Scholar
  24. 24.
    Piskunowicz M, Świętoń D, Rybczyńska D, Czarniak P, Szarmach A, Kaszubowski M, Szurowska E (2016) Comparison of voiding cystourethrography and urosonography with second-generation contrast agents in simultaneous prospective study. J Ultrasonogr 16(67):339–347.
  25. 25.
    Ntoulia A, Back SJ, Shellikeri S, Poznick L, Morgan T, Kerwood J, Christopher Edgar J, Bellah RD, Reid JR, Jaramillo D, Canning DA, Darge K (2018) Contrast-enhanced voiding urosonography (ceVUS) with the intravesical administration of the ultrasound contrast agent Optison™ for vesicoureteral reflux detection in children: a prospective clinical trial. Pediatr Radiol 48(2):216–226. CrossRefPubMedGoogle Scholar
  26. 26.
    Hosmer DW, Lemeshow S (2000) Applied logistic regression, 2nd edn. Wiley, New York, pp 160–163.
  27. 27.
    Papadopoulou F, Ntoulia A, Siomou E, Darge K (2014) Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux: prospective evaluation of contrast safety in 1,010 children. Pediatr Radiol 44(6):719–728. CrossRefPubMedGoogle Scholar
  28. 28.
    Duran C, del Riego J, Riera L, Martin C, Serrano C, Palaña P (2012) Voiding urosonography including urethrosonography: high-quality examinations with an optimised procedure using a second-generation US contrast agent. Pediatr Radiol 42(6):660–667. CrossRefPubMedGoogle Scholar
  29. 29.
    Darge K, Zieger B, Ronsrscheider W, Ghods S, Wunrsche T, Troeger J (2001) Contrast-enhanced harmonic imaging for the diagnosis of vesicoureteral reflux in pediatric population. AJR Am J Roentgenol. 177(6):1411–1415CrossRefGoogle Scholar
  30. 30.
    Riccabona M (2012) Application of a second-generation US contrast agent in infants and children—a European questionnaire-based survey. Pediatr Radiol 42(12):1471–1480. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Michael E. Chua
    • 1
    Email author
  • Jonathan S. Mendoza
    • 1
  • Jessica M. Ming
    • 2
  • Jun S. Dy
    • 1
  • Odina Gomez
    • 3
  1. 1.Section of Pediatric UrologyInstitute of Urology, St. Luke’s Medical CenterQuezon CityPhilippines
  2. 2.Section of Urology, Department of SurgeryUniversity of New MexicoAlbuquerqueUSA
  3. 3.Section of Pediatric ImagingInstitute of Radiology, St. Luke’s Medical CenterQuezon CityPhilippines

Personalised recommendations