Pediatric Urology The Long-term Incidence of Urinary Tract Infection After Endoscopic Management of Vesicoureteral Reflux Adrienne M. Heckler, Jennifer Sung, Sean Watters, Ann Martinez Acevedo, Michael Conlin, and Steven Skoog OBJECTIVE MATERIALS AND METHODS
RESULTS
CONCLUSION
To evaluate the long-term urinary tract infection (UTI) rates after endoscopic correction of vesicoureteral reflux and the possible risk factors for urinary infection. A retrospective study of patients who underwent endoscopic management of vesicoureteral reflux at a single institution from 2001 to 2011 was performed. Patients were followed up for a minimum of 1 year. Voiding cystourethrograms were completed 3 months postoperatively. UTI questionnaire pertaining to the patient’s UTI history before and after the surgery was mailed to each patient. Data were first evaluated looking only at culture-confirmed UTIs, and a second analysis included all patient-reported and culture-confirmed urinary infections. Factors considered in the analysis included sex, age, preoperative dimercaptosuccinic acid (DMSA) scan, reflux on postoperative voiding cystourethrogram, voiding dysfunction, and preoperative reflux grade. Data on 175 patients for a minimum of 1 year were collected. There were 34 of 175 confirmed UTIs after endoscopic management, and 11 confirmed febrile UTIs. There were no significant predictors of febrile or afebrile UTIs in this group. Fifty-three of 175 patients (30%) experienced any UTI, 19 of which were febrile (10%). In this group, recurrent reflux was the only significant predictor of UTI (P ¼ .03) and febrile UTIs (P ¼ .04). Patients with more UTIs preoperatively were more likely to have a postoperative febrile UTI. Rates of UTI and febrile UTI in endoscopic management are similar and no better than those for open ureteral reimplantation. Longer follow-up suggests an association of recurrent reflux and preoperative UTI rates as predictors of postoperative febrile UTIs. These patients benefit from closer postoperative observation. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
P
rimary vesicoureteral reflux (VUR) is the abnormal flow of urine from the bladder into the ureter and (in many cases) the renal pelvis. It usually presents in children as a febrile urinary tract infection (UTI). The primary goal of management, whether surgical or medical, is preventing recurrent febrile pyelonephritis and associated renal scarring. The gold standard for surgical management of VUR is open ureteral reimplantation. Ureteral reimplantation has been well studied with randomized prospective trials. These reveal a successful correction of VUR in 95% of patients, a postoperative UTI rate of 30%, and an 8% rate of postoperative febrile UTIs.2-7 There are fewer studies evaluating endoscopic surgical management of VUR. These suggest postoperative UTI rates ranging from 6% to 45% and febrile UTIs of 0.75%-8%. These studies generally have limited number of patients with short
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Oregon Health & Science University, Portland, OR Reprint requests: Steven Skoog, M.D., Oregon Health & Science University, 3181 SW Sam Jackson Park Road, CDW6, Portland, OR 97239. E-mail: [email protected] Submitted: September 12, 2013, accepted (with revisions): December 26, 2013
ª 2014 Elsevier Inc. All Rights Reserved
follow-up.8,10-12 The goal of this study was to determine the rate of UTIs after endoscopic correction of VUR and evaluate possible contributing risk factors.
METHODS We reviewed our prospectively collected database containing data on all patients undergoing endoscopic injection for VUR at Oregon Health & Science University (OHSU). This data repository is approved by the institutional review board (IRB) at OHSU. We obtained separate approval from the OHSU IRB for the conduct of this review. We limited our review to patients treated between 2001 and 2011. We excluded patients treated for secondary VUR. Patients with duplicated ureters and bladder and bowel dysfunction (BBD) were not excluded, for a total of 175 study patients. Most of the patients in the database presented with febrile UTIs preoperatively. However, except with response to the questionnaire, these data were not included in our database and is therefore not quantified. The average patient age at surgery was 6 years, and the range was 1-23 years. The total number of treated patients with VUR was 172; complete data were not recorded in 3 of the study patients. Sixty-seven of these patients had BBD. All patients with BBD were actively treated with behavioral modifications, including timed voiding and 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.045
1
Figure 1. Vesicoureteral reflux patient questionnaire.
micturition alarms and appropriate pharmaceutical therapies before and after the procedure. Patients were placed on antibiotic prophylaxis before the procedure and maintained until their postoperative voiding cystourethrogram (VCUG) demonstrated resolution of VUR. Indications for surgery included patient and/or family preference, breakthrough febrile UTIs on either observation or antibiotic prophylaxis, persistent VUR, solitary kidney with VUR, signs of new renal scarring on dimercaptosuccinic acid (DMSA) scan, or renal insufficiency on initial visit. Patients underwent a hydrodistention-implantation technique (HIT) or subureteric transurethral injection (STING) procedure with endoscopic repair of VUR according to the techniques previously described.9,13 The postoperative course included a 3-month follow-up with VCUG, ultrasound, and urinalysis. A follow-up 2
at 1 year with assessment of previous UTI, urinalysis, and ultrasound was performed. Patients were then instructed to re-establish contact for any febrile UTI events, at which time, a repeat VCUG was performed. Patients who had postoperative voiding dysfunction, renal insufficiency, or persistent UTIs were followed up for longer than a year as needed. In 2011, a questionnaire composed of 12 questions pertaining to details of UTIs before and after the surgery was sent by mail to all patients (Fig. 1). Families who did not respond to the mailed questionnaire were contacted by phone where a verbal version of the questionnaire was completed. Consent to participate in the study was sent and collected for each patient. The primary care physician was contacted for anyone with a postoperative UTI, as determined by either questionnaire or follow-up in our clinic. The UROLOGY
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Table 1. Multivariate analysis of all reported urinary tract infections Odds Ratio Std. Err. P Value
UTI Sex Voiding dysfunction DMSA scan Age Recur reflux Duplex system
CI
6.5 1.37
7.95 0.79
.12 .58
0.62-70 0.44-4.3
1.49 1.09 3.4 1
0.95 0.09 2.02 —
.53 .26 .03 —
0.42-5.2 0.93-1.3 1.11-10.9 —
CI, confidence interval; DMSA, dimercaptosuccinic acid; UTI, urinary tract infection.
primary care physician’s records concerning the UTIs were obtained, including urinalysis, urine cultures, and correlating progress notes. UTIs were considered confirmed if there was a urinalysis positive for leukocyte esterase in a symptomatic patient and/ or a urine culture positive for >10,000 CFU/mL of a single organism. DMSA findings, VUR grade, postoperative renal ultrasound and VCUG findings, number of UTIs and febrile UTIs before and after procedure, presence of BBD, duplicated ureters, and questionnaire results were entered into an IRB-approved secure online database. Follow-up time was defined as either the last clinic visit or the date the questionnaire was completed. Statistical analysis was first completed only on patients with a confirmed UTI. A repeat analysis was then completed on all patients reporting a UTI. Patient characteristics evaluated are those thought to contribute to incidence of UTIs and VUR resolution.6,14-16 These included patient age, sex, previous UTIs, preprocedure VUR grade, presence of BBD, and scarring on preoperative DMSA scan. We performed t test, chi-squared, and Fisher’s exact tests for univariate comparison of these variables and questionnaire results. Multivariate analysis was completed via logistic regression. All statistical analyses were performed using Stata 12.1 (StataCorp LP, College Station, TX).
RESULTS A total of 175 patients were followed up for a minimum of 1 year with a mean follow-up time of 37 months (range, 12-112). Sixty-six patients returned questionnaires by either mail or phone. Reflux ranged from grade 2-4 with 18 male and 157 female patients. Seventy-four percent of all patients had VUR resolution postoperatively as noted on the VCUG at 3 months. There were 86 unilateral refluxing ureters and 189 bilateral refluxing ureters. Nineteen percent of all unilateral and bilateral refluxing patients had a maximum reflux grade of 4; 51% had a maximum reflux grade of 3, and 30% had a maximum reflux grade of 2. Sixty-five percent of reported infections were confirmed. A total of 175 patients (30%) reported UTIs with 19 (10%) febrile UTIs. Results of multivariable analysis demonstrated no significant correlations with preoperative characteristics (age, sex, reflux grade, BBD, and duplex systems) when analyzing confirmed UTIs alone. However, recurrent VUR correlated significantly with both postoperative UTI and febrile UTI when all reported UTIs were included in the analysis (P ¼ .03; .04; Table 1 and Fig. 2). Patients with a higher number of UROLOGY
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Figure 2. Multivariate analysis of all reported febrile urinary tract infections (UTIs). CI, confidence interval. (Color version available online.)
preoperative UTIs (reported by questionnaire) were also more likely to have postoperative febrile UTIs on the basis of questionnaire responses (Fig. 3).
COMMENT Endoscopic management has become an increasingly popular option for the treatment of VUR. It is a procedure that allows parents to avoid long-term prophylaxis for their children, without committing to open surgical reconstruction. Studies have shown excellent success in immediate resolution of VUR with endoscopic surgery.8 However, despite its increasing prevalence, there remains a wide range of published UTI rates and little information on how sustainable the repair is.10,17 One randomized trial comparing medical management with endoscopic treatment showed 22% of surgical patients had postprocedure UTIs. The power was limited, however, including only 61 patients, and details including febrile vs afebrile UTIs were also lacking.18 A metaanalysis involving 5527 patients found the resolution of reflux to be 78.5% for grade I/II VUR, 72% for grade III, and 63% and 51% for grades IV and V, respectively, after a single endoscopic treatment. They noted a postprocedure pyelonephritis rate of 0.75%, and cystitis rate of 6%.8 Few of the studies included an incidence for UTI, and there is no mention of length of follow-up or whether patients with infection had persistent reflux. The 2010 American Urological Association guidelines report an estimated 30% of open ureteral reimplant patients will experience cystitis, 10% a febrile UTI.1 In our review, the rate of postprocedure UTIs in the endoscopic population was comparable with those reported for open repair. Although reports have linked voiding dysfunction and BBD with recurrent UTIs in children, it did not contribute significantly in our study.19-21 Koff et al demonstrated the presence of BBD in 43% of patients with primary VUR. Seventy-eight percent of UTIs after surgical correction occurred in BBD patients. In their 3
Figure 3. Box chart comparing questionnaire responses to preprocedure urinary tract infections (UTIs) on questionnaire to reported postprocedure febrile urinary tract infections. (Color version available online.)
study, this was the only population to experience unsuccessful surgical outcomes.20 Subsequent metaanalysis of the incidence of UTI during follow-up of open or endoscopic surgery was 22.6% for children with BBD and 4.8% for children without BBD.1 Unique to our study, all patients presenting with BBD and diagnosed with VUR were treated with behavioral and pharmacologic interventions. Management is maintained throughout their treatment regimens and continued after surgery when warranted. This therapy may explain why BBD did not predict continued infections. These results suggest appropriate management of these patients may indeed remove them from a higher-risk category for recurrent infections after surgical correction of their reflux. Further studies to support this may prove beneficial. Current guidelines describe a lack of validated treatment recommendations for BBD or an adequate grading system.1 Scarring on DMSA has also been shown to correlate with recurrent UTIs.22,23 This association was not demonstrated in this population. Of note, scans were not obtained on every patient, and so sufficient data may not have been available to complete this analysis. The difficulty in ascertaining adequate urine specimens in children has been described.15 Many patients with a known history of recurrent UTIs are treated on the basis of symptoms alone or urinalysis alone without available culture. Similar studies looking at UTI rates have restricted their definition of UTI to culture-proven events only, potentially missing a large cohort of patients and underestimating the actual number of events in an existing population.10 In a patient population in which parents have experienced multiple UTIs in their children, we believe it is reliable and necessary to include patientreported events in our analysis when they report being treated with antibiotics for a UTI. This is supported by the findings of significant associations with recurrent reflux and UTIs, only when the subjective and objective data are evaluated together. 4
The limitations of this study involve its retrospective nature. Questionnaires were not completed on all the patients. We assumed that no follow-up in our clinic meant no infections after surgical intervention. However, a significant amount of patients’ information may not have been available after the last clinic appointment. This could lead to a selection bias in our results and a lower postprocedure UTI rate. Our practice is to perform a VCUG in all patients at the 3-month postprocedure appointment and in the event of a febrile UTI. Patients with persistent reflux are offered repeat endoscopic treatment or open ureteral reimplantation. Without a VCUG on all follow-up patients, the incidence of recurrent reflux and the long-term reliability of endoscopic management cannot be accurately ascertained from these data. However, our significant association between recurrent febrile UTIs and reflux on follow-up VCUG suggests a possible relationship. Snodgrass et al in 2008 showed a 50% recurrent reflux rate in their postprocedure febrile UTI population. These findings are supported in other reviews.10 However, a recent publication by Dwyer et al 2013 found persistent reflux was not a predictor of postoperative febrile UTI. However, the longest follow-up was 5 years with a median of 28 months, and only 9 of the 16 febrile UTI patients received a repeat VCUG at time of infection.10,17,24 Given these studies, it would be interesting to have subsequent evaluation on the long-term surgical correction with endoscopic repair. Possibly, repeating VCUG’s after the first year on high-risk patients—those with frequent preoperative UTIs—may prove informative.
CONCLUSION A significantly higher number of patients with positive 1 year postprocedure VCUGs were prone to recurrent UTIs. In addition, these data show patients with more preoperative UTIs continued to be at a higher risk of a postoperative UTI. Ultimately, these results suggest a concern for recurrent infections in patients undergoing this procedure—most specifically in those with reflux postprocedure or with a high incidence of preprocedure UTIs. This study does not answer the question of whether the reflux is persistent or recurrent. Most available studies comment only on the immediate success of this procedure. With more and more physicians choosing to treat VUR endoscopically, future reviews would benefit from delineating long-term anatomic success of endoscopic management further. Regardless, patients with reflux on follow-up VCUG or with a high incidence of preprocedure UTIs warrant closer follow-up and surveillance. References 1. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184:1134-1144. 2. Austin JC, Cooper CS. Vesicoureteral reflux: surgical approaches. Urol Clin North Am. 2004;31:543-557.
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3. Duckett JW, Walker RD, Weiss R. Surgical results: International Reflux Study in ChildreneUnited States branch. J Urol. 1992;148(5 Pt 2):1674-1675. 4. Wacksman J. Initial results with the Cohen cross-trigonal ureteroneocystotomy. J Urol. 1983;129:1198-1199. 5. Jodal U, Koskimies O, Hanson E, et al. Infection pattern in children with vesicoureteral reflux randomly allocated to operation or longterm antibacterial prophylaxis. The International Reflux Study in Children. J Urol. 1992;148(5 Pt 2):1650-1652. 6. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol. 1997;157:18461851. 7. Weiss R, Duckett J, Spitzer A. Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol. 1992;148(5 Pt 2): 1667-1673. 8. Elder JS, Diaz M, Caldamone AA, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;175:716-722. 9. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004;171(6 Pt 1):2413-2416. 10. Sedberry-Ross S, Rice DC, Pohl HG, et al. Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol. 2008;180(4 Suppl):1605-1609; discussion 1610. 11. Wadie GM, Moriarty KP. The impact of vesicoureteral reflux treatment on the incidence of urinary tract infection. Pediatr Nephrol. 2012;27:529-538. 12. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics. 2010; 125:1010-1019.
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13. Sung J, Skoog S. Surgical management of vesicoureteral reflux in children. Pediatr Nephrol. 2012;27:551-561. 14. Farhat W, McLorie G, Geary D, et al. The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis. J Urol. 2000;164(3 Pt 2):1057-1060. 15. Shah G, Upadhyay J. Controversies in the diagnosis and management of urinary tract infections in children. Paediatr Drugs. 2005;7: 339-346. 16. Habib S. Highlights for management of a child with a urinary tract infection. Int J Pediatr. 2012;2012:943653. 17. Chi A, Gupta A, Snodgrass W. Urinary tract infection following successful dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol. 2008;179:1966-1969. 18. Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr. 2002;140:230-234. 19. Hansson S. Urinary incontinence in children and associated problems. Scand J Urol Nephrol Suppl. 1992;141:47-55; discussion 56-7. 20. Koff SA, Murtagh DS. The uninhibited bladder in children: effect of treatment on recurrence of urinary infection and on vesicoureteral reflux resolution. J Urol. 1983;130:1138-1141. 21. Snodgrass W. Relationship of voiding dysfunction to urinary tract infection and vesicoureteral reflux in children. Urology. 1991;38: 341-344. 22. Mingin GC, Nguyen HT, Baskin LS, Harlan S. Abnormal dimercapto-succinic acid scans predict an increased risk of breakthrough infection in children with vesicoureteral reflux. J Urol. 2004;172:1075-1077; discussion 1077. 23. Panaretto K, Craig J, Knight J, et al. Risk factors for recurrent urinary tract infection in preschool children. J Paediatr Child Health. 1999;35:454-459. 24. Dwyer ME, Husmann DA, Rathbun SR, et al. Febrile urinary tract infections after ureteroneocystostomy and subureteral injection of dextranomer/hyaluronic acid for vesicoureteral refluxedo choice of procedure and success matter? J Urol. 2013;189:275-282.
5
RESULTS
CONCLUSION
To evaluate the long-term urinary tract infection (UTI) rates after endoscopic correction of vesicoureteral reflux and the possible risk factors for urinary infection. A retrospective study of patients who underwent endoscopic management of vesicoureteral reflux at a single institution from 2001 to 2011 was performed. Patients were followed up for a minimum of 1 year. Voiding cystourethrograms were completed 3 months postoperatively. UTI questionnaire pertaining to the patient’s UTI history before and after the surgery was mailed to each patient. Data were first evaluated looking only at culture-confirmed UTIs, and a second analysis included all patient-reported and culture-confirmed urinary infections. Factors considered in the analysis included sex, age, preoperative dimercaptosuccinic acid (DMSA) scan, reflux on postoperative voiding cystourethrogram, voiding dysfunction, and preoperative reflux grade. Data on 175 patients for a minimum of 1 year were collected. There were 34 of 175 confirmed UTIs after endoscopic management, and 11 confirmed febrile UTIs. There were no significant predictors of febrile or afebrile UTIs in this group. Fifty-three of 175 patients (30%) experienced any UTI, 19 of which were febrile (10%). In this group, recurrent reflux was the only significant predictor of UTI (P ¼ .03) and febrile UTIs (P ¼ .04). Patients with more UTIs preoperatively were more likely to have a postoperative febrile UTI. Rates of UTI and febrile UTI in endoscopic management are similar and no better than those for open ureteral reimplantation. Longer follow-up suggests an association of recurrent reflux and preoperative UTI rates as predictors of postoperative febrile UTIs. These patients benefit from closer postoperative observation. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
P
rimary vesicoureteral reflux (VUR) is the abnormal flow of urine from the bladder into the ureter and (in many cases) the renal pelvis. It usually presents in children as a febrile urinary tract infection (UTI). The primary goal of management, whether surgical or medical, is preventing recurrent febrile pyelonephritis and associated renal scarring. The gold standard for surgical management of VUR is open ureteral reimplantation. Ureteral reimplantation has been well studied with randomized prospective trials. These reveal a successful correction of VUR in 95% of patients, a postoperative UTI rate of 30%, and an 8% rate of postoperative febrile UTIs.2-7 There are fewer studies evaluating endoscopic surgical management of VUR. These suggest postoperative UTI rates ranging from 6% to 45% and febrile UTIs of 0.75%-8%. These studies generally have limited number of patients with short
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Oregon Health & Science University, Portland, OR Reprint requests: Steven Skoog, M.D., Oregon Health & Science University, 3181 SW Sam Jackson Park Road, CDW6, Portland, OR 97239. E-mail: [email protected] Submitted: September 12, 2013, accepted (with revisions): December 26, 2013
ª 2014 Elsevier Inc. All Rights Reserved
follow-up.8,10-12 The goal of this study was to determine the rate of UTIs after endoscopic correction of VUR and evaluate possible contributing risk factors.
METHODS We reviewed our prospectively collected database containing data on all patients undergoing endoscopic injection for VUR at Oregon Health & Science University (OHSU). This data repository is approved by the institutional review board (IRB) at OHSU. We obtained separate approval from the OHSU IRB for the conduct of this review. We limited our review to patients treated between 2001 and 2011. We excluded patients treated for secondary VUR. Patients with duplicated ureters and bladder and bowel dysfunction (BBD) were not excluded, for a total of 175 study patients. Most of the patients in the database presented with febrile UTIs preoperatively. However, except with response to the questionnaire, these data were not included in our database and is therefore not quantified. The average patient age at surgery was 6 years, and the range was 1-23 years. The total number of treated patients with VUR was 172; complete data were not recorded in 3 of the study patients. Sixty-seven of these patients had BBD. All patients with BBD were actively treated with behavioral modifications, including timed voiding and 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.045
1
Figure 1. Vesicoureteral reflux patient questionnaire.
micturition alarms and appropriate pharmaceutical therapies before and after the procedure. Patients were placed on antibiotic prophylaxis before the procedure and maintained until their postoperative voiding cystourethrogram (VCUG) demonstrated resolution of VUR. Indications for surgery included patient and/or family preference, breakthrough febrile UTIs on either observation or antibiotic prophylaxis, persistent VUR, solitary kidney with VUR, signs of new renal scarring on dimercaptosuccinic acid (DMSA) scan, or renal insufficiency on initial visit. Patients underwent a hydrodistention-implantation technique (HIT) or subureteric transurethral injection (STING) procedure with endoscopic repair of VUR according to the techniques previously described.9,13 The postoperative course included a 3-month follow-up with VCUG, ultrasound, and urinalysis. A follow-up 2
at 1 year with assessment of previous UTI, urinalysis, and ultrasound was performed. Patients were then instructed to re-establish contact for any febrile UTI events, at which time, a repeat VCUG was performed. Patients who had postoperative voiding dysfunction, renal insufficiency, or persistent UTIs were followed up for longer than a year as needed. In 2011, a questionnaire composed of 12 questions pertaining to details of UTIs before and after the surgery was sent by mail to all patients (Fig. 1). Families who did not respond to the mailed questionnaire were contacted by phone where a verbal version of the questionnaire was completed. Consent to participate in the study was sent and collected for each patient. The primary care physician was contacted for anyone with a postoperative UTI, as determined by either questionnaire or follow-up in our clinic. The UROLOGY
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Table 1. Multivariate analysis of all reported urinary tract infections Odds Ratio Std. Err. P Value
UTI Sex Voiding dysfunction DMSA scan Age Recur reflux Duplex system
CI
6.5 1.37
7.95 0.79
.12 .58
0.62-70 0.44-4.3
1.49 1.09 3.4 1
0.95 0.09 2.02 —
.53 .26 .03 —
0.42-5.2 0.93-1.3 1.11-10.9 —
CI, confidence interval; DMSA, dimercaptosuccinic acid; UTI, urinary tract infection.
primary care physician’s records concerning the UTIs were obtained, including urinalysis, urine cultures, and correlating progress notes. UTIs were considered confirmed if there was a urinalysis positive for leukocyte esterase in a symptomatic patient and/ or a urine culture positive for >10,000 CFU/mL of a single organism. DMSA findings, VUR grade, postoperative renal ultrasound and VCUG findings, number of UTIs and febrile UTIs before and after procedure, presence of BBD, duplicated ureters, and questionnaire results were entered into an IRB-approved secure online database. Follow-up time was defined as either the last clinic visit or the date the questionnaire was completed. Statistical analysis was first completed only on patients with a confirmed UTI. A repeat analysis was then completed on all patients reporting a UTI. Patient characteristics evaluated are those thought to contribute to incidence of UTIs and VUR resolution.6,14-16 These included patient age, sex, previous UTIs, preprocedure VUR grade, presence of BBD, and scarring on preoperative DMSA scan. We performed t test, chi-squared, and Fisher’s exact tests for univariate comparison of these variables and questionnaire results. Multivariate analysis was completed via logistic regression. All statistical analyses were performed using Stata 12.1 (StataCorp LP, College Station, TX).
RESULTS A total of 175 patients were followed up for a minimum of 1 year with a mean follow-up time of 37 months (range, 12-112). Sixty-six patients returned questionnaires by either mail or phone. Reflux ranged from grade 2-4 with 18 male and 157 female patients. Seventy-four percent of all patients had VUR resolution postoperatively as noted on the VCUG at 3 months. There were 86 unilateral refluxing ureters and 189 bilateral refluxing ureters. Nineteen percent of all unilateral and bilateral refluxing patients had a maximum reflux grade of 4; 51% had a maximum reflux grade of 3, and 30% had a maximum reflux grade of 2. Sixty-five percent of reported infections were confirmed. A total of 175 patients (30%) reported UTIs with 19 (10%) febrile UTIs. Results of multivariable analysis demonstrated no significant correlations with preoperative characteristics (age, sex, reflux grade, BBD, and duplex systems) when analyzing confirmed UTIs alone. However, recurrent VUR correlated significantly with both postoperative UTI and febrile UTI when all reported UTIs were included in the analysis (P ¼ .03; .04; Table 1 and Fig. 2). Patients with a higher number of UROLOGY
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Figure 2. Multivariate analysis of all reported febrile urinary tract infections (UTIs). CI, confidence interval. (Color version available online.)
preoperative UTIs (reported by questionnaire) were also more likely to have postoperative febrile UTIs on the basis of questionnaire responses (Fig. 3).
COMMENT Endoscopic management has become an increasingly popular option for the treatment of VUR. It is a procedure that allows parents to avoid long-term prophylaxis for their children, without committing to open surgical reconstruction. Studies have shown excellent success in immediate resolution of VUR with endoscopic surgery.8 However, despite its increasing prevalence, there remains a wide range of published UTI rates and little information on how sustainable the repair is.10,17 One randomized trial comparing medical management with endoscopic treatment showed 22% of surgical patients had postprocedure UTIs. The power was limited, however, including only 61 patients, and details including febrile vs afebrile UTIs were also lacking.18 A metaanalysis involving 5527 patients found the resolution of reflux to be 78.5% for grade I/II VUR, 72% for grade III, and 63% and 51% for grades IV and V, respectively, after a single endoscopic treatment. They noted a postprocedure pyelonephritis rate of 0.75%, and cystitis rate of 6%.8 Few of the studies included an incidence for UTI, and there is no mention of length of follow-up or whether patients with infection had persistent reflux. The 2010 American Urological Association guidelines report an estimated 30% of open ureteral reimplant patients will experience cystitis, 10% a febrile UTI.1 In our review, the rate of postprocedure UTIs in the endoscopic population was comparable with those reported for open repair. Although reports have linked voiding dysfunction and BBD with recurrent UTIs in children, it did not contribute significantly in our study.19-21 Koff et al demonstrated the presence of BBD in 43% of patients with primary VUR. Seventy-eight percent of UTIs after surgical correction occurred in BBD patients. In their 3
Figure 3. Box chart comparing questionnaire responses to preprocedure urinary tract infections (UTIs) on questionnaire to reported postprocedure febrile urinary tract infections. (Color version available online.)
study, this was the only population to experience unsuccessful surgical outcomes.20 Subsequent metaanalysis of the incidence of UTI during follow-up of open or endoscopic surgery was 22.6% for children with BBD and 4.8% for children without BBD.1 Unique to our study, all patients presenting with BBD and diagnosed with VUR were treated with behavioral and pharmacologic interventions. Management is maintained throughout their treatment regimens and continued after surgery when warranted. This therapy may explain why BBD did not predict continued infections. These results suggest appropriate management of these patients may indeed remove them from a higher-risk category for recurrent infections after surgical correction of their reflux. Further studies to support this may prove beneficial. Current guidelines describe a lack of validated treatment recommendations for BBD or an adequate grading system.1 Scarring on DMSA has also been shown to correlate with recurrent UTIs.22,23 This association was not demonstrated in this population. Of note, scans were not obtained on every patient, and so sufficient data may not have been available to complete this analysis. The difficulty in ascertaining adequate urine specimens in children has been described.15 Many patients with a known history of recurrent UTIs are treated on the basis of symptoms alone or urinalysis alone without available culture. Similar studies looking at UTI rates have restricted their definition of UTI to culture-proven events only, potentially missing a large cohort of patients and underestimating the actual number of events in an existing population.10 In a patient population in which parents have experienced multiple UTIs in their children, we believe it is reliable and necessary to include patientreported events in our analysis when they report being treated with antibiotics for a UTI. This is supported by the findings of significant associations with recurrent reflux and UTIs, only when the subjective and objective data are evaluated together. 4
The limitations of this study involve its retrospective nature. Questionnaires were not completed on all the patients. We assumed that no follow-up in our clinic meant no infections after surgical intervention. However, a significant amount of patients’ information may not have been available after the last clinic appointment. This could lead to a selection bias in our results and a lower postprocedure UTI rate. Our practice is to perform a VCUG in all patients at the 3-month postprocedure appointment and in the event of a febrile UTI. Patients with persistent reflux are offered repeat endoscopic treatment or open ureteral reimplantation. Without a VCUG on all follow-up patients, the incidence of recurrent reflux and the long-term reliability of endoscopic management cannot be accurately ascertained from these data. However, our significant association between recurrent febrile UTIs and reflux on follow-up VCUG suggests a possible relationship. Snodgrass et al in 2008 showed a 50% recurrent reflux rate in their postprocedure febrile UTI population. These findings are supported in other reviews.10 However, a recent publication by Dwyer et al 2013 found persistent reflux was not a predictor of postoperative febrile UTI. However, the longest follow-up was 5 years with a median of 28 months, and only 9 of the 16 febrile UTI patients received a repeat VCUG at time of infection.10,17,24 Given these studies, it would be interesting to have subsequent evaluation on the long-term surgical correction with endoscopic repair. Possibly, repeating VCUG’s after the first year on high-risk patients—those with frequent preoperative UTIs—may prove informative.
CONCLUSION A significantly higher number of patients with positive 1 year postprocedure VCUGs were prone to recurrent UTIs. In addition, these data show patients with more preoperative UTIs continued to be at a higher risk of a postoperative UTI. Ultimately, these results suggest a concern for recurrent infections in patients undergoing this procedure—most specifically in those with reflux postprocedure or with a high incidence of preprocedure UTIs. This study does not answer the question of whether the reflux is persistent or recurrent. Most available studies comment only on the immediate success of this procedure. With more and more physicians choosing to treat VUR endoscopically, future reviews would benefit from delineating long-term anatomic success of endoscopic management further. Regardless, patients with reflux on follow-up VCUG or with a high incidence of preprocedure UTIs warrant closer follow-up and surveillance. References 1. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184:1134-1144. 2. Austin JC, Cooper CS. Vesicoureteral reflux: surgical approaches. Urol Clin North Am. 2004;31:543-557.
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3. Duckett JW, Walker RD, Weiss R. Surgical results: International Reflux Study in ChildreneUnited States branch. J Urol. 1992;148(5 Pt 2):1674-1675. 4. Wacksman J. Initial results with the Cohen cross-trigonal ureteroneocystotomy. J Urol. 1983;129:1198-1199. 5. Jodal U, Koskimies O, Hanson E, et al. Infection pattern in children with vesicoureteral reflux randomly allocated to operation or longterm antibacterial prophylaxis. The International Reflux Study in Children. J Urol. 1992;148(5 Pt 2):1650-1652. 6. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol. 1997;157:18461851. 7. Weiss R, Duckett J, Spitzer A. Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol. 1992;148(5 Pt 2): 1667-1673. 8. Elder JS, Diaz M, Caldamone AA, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;175:716-722. 9. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004;171(6 Pt 1):2413-2416. 10. Sedberry-Ross S, Rice DC, Pohl HG, et al. Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol. 2008;180(4 Suppl):1605-1609; discussion 1610. 11. Wadie GM, Moriarty KP. The impact of vesicoureteral reflux treatment on the incidence of urinary tract infection. Pediatr Nephrol. 2012;27:529-538. 12. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics. 2010; 125:1010-1019.
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13. Sung J, Skoog S. Surgical management of vesicoureteral reflux in children. Pediatr Nephrol. 2012;27:551-561. 14. Farhat W, McLorie G, Geary D, et al. The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis. J Urol. 2000;164(3 Pt 2):1057-1060. 15. Shah G, Upadhyay J. Controversies in the diagnosis and management of urinary tract infections in children. Paediatr Drugs. 2005;7: 339-346. 16. Habib S. Highlights for management of a child with a urinary tract infection. Int J Pediatr. 2012;2012:943653. 17. Chi A, Gupta A, Snodgrass W. Urinary tract infection following successful dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol. 2008;179:1966-1969. 18. Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr. 2002;140:230-234. 19. Hansson S. Urinary incontinence in children and associated problems. Scand J Urol Nephrol Suppl. 1992;141:47-55; discussion 56-7. 20. Koff SA, Murtagh DS. The uninhibited bladder in children: effect of treatment on recurrence of urinary infection and on vesicoureteral reflux resolution. J Urol. 1983;130:1138-1141. 21. Snodgrass W. Relationship of voiding dysfunction to urinary tract infection and vesicoureteral reflux in children. Urology. 1991;38: 341-344. 22. Mingin GC, Nguyen HT, Baskin LS, Harlan S. Abnormal dimercapto-succinic acid scans predict an increased risk of breakthrough infection in children with vesicoureteral reflux. J Urol. 2004;172:1075-1077; discussion 1077. 23. Panaretto K, Craig J, Knight J, et al. Risk factors for recurrent urinary tract infection in preschool children. J Paediatr Child Health. 1999;35:454-459. 24. Dwyer ME, Husmann DA, Rathbun SR, et al. Febrile urinary tract infections after ureteroneocystostomy and subureteral injection of dextranomer/hyaluronic acid for vesicoureteral refluxedo choice of procedure and success matter? J Urol. 2013;189:275-282.
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