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Opposing Views
Opposing Views
PIC Cystography: A Selective Approach to the Diagnosis of Vesicoureteral Reflux WE cannot deny the positive impact that has been made on the incidence of severe acquired renal cortical scarring through the early diagnosis of vesicoureteral reflux (VUR) and the prevention of recurrent acute pyelonephritis (APN) via prophylactic antibiotics and/or surgical intervention as indicated. Proponents of the PIC (positioned instillation of contrast) cystogram advocate its use on the basis that febrile urinary tract infection (UTI) is not associated with VUR in up to 65% of cases evaluated by standard voiding cystourethrography (VCUG) and, thus, the sensitivity of VCUG for the detection of VUR is wanting, and that all VUR should be identified and treated— which is conveniently accomplished under the same anesthetic by endoscopic means. The standard evaluation of febrile UTI in children has long included ultrasonography and VCUG. Using this approach, the prevalence of VUR in children presenting with febrile UTI varies between 25% and 50% (mean 35%) depending on the timing of the VCUG and the number of fill-void cycles performed. Using dimercapto-succinic acid (DMSA) renal scans to document the presence of APN, Majd and Rushton performed a VCUG during hospitalization and found VUR in only 37% of patients with renal cortical abnormalities.1 Other studies have shown that when a VCUG is delayed 4 to 6 weeks following presentation for febrile UTI the diagnosis of VUR will be missed in as many as 28.5% of children. In addition, it has been reported that grades III and higher VUR can be missed in up to a third of patients undergoing only 1 filling cycle, whereas generally 2 filling cycles increase the yield of identifying low to moderate grade VUR.2,3 While it is true that VUR can elude diagnosis depending on the timing and technique used during VCUG, it is illogical to argue that VUR that can only be demonstrated by positioning a stream of contrast at the ureteral orifice is not iatrogenic. Children with presumed PIC positive VUR and uropathogenic bacteria that infect the upper tracts do not have 0022-5347/09/1824-1263/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
the benefit of a cystoscope to gain access to the upper urinary tract. Even so, when PIC cystography is performed the VUR that is identified is generally of low grade and no child is offered the opportunity to undergo long-term followup to assess the impact of maturation and/or intervention for voiding dysfunction before surgery is performed.4,5 Assuming that occult VUR does exist, what is the evidence to support that all VUR, even that which presents with UTI, requires surgical intervention? Cooper et al reported their observations on 51 children whose prophylaxis was discontinued despite persistent VUR.6 During a mean followup of 3.7 years VUR resolved in 19.6% of the children. UTI recurred in 11.8% (6 of 51) of children following cessation of prophylaxis, prompting reimplantation in 5 of the 6 children but in no child was acquired renal cortical scarring documented. Clearly there is a subset of children at risk for recurrent UTI and renal scarring with and without VUR, which should be the focus of intervention, while the majority of children may do well without antibiotics or surgery for VUR. Recently, several studies have advocated the concept of a “top down” approach to the evaluation of children with UTIs.7,8 This selective approach focuses on renal status rather than the presence or absence of VUR. The goal of this approach is to identify only those children with clinically significant VUR, defined as those at risk for renal scarring or recurrent febrile UTIs. It begins with a DMSA scan, reserving evaluation with a VCUG only for those who have abnormal DMSA findings or subsequent recurrent UTIs. This approach is supported by prior clinical studies of abnormal DMSA findings in 80% to 90% of children with VUR and febrile UTIs, including almost all with grade III or higher VUR.7 In a recent prospective study this approach was analyzed in 290 patients (79% with fever 38.5C or greater).9 DMSA scans within 2 weeks of the infection demonstrated abnormalities in 51% of patients, including 96% (26 of 27) of those with grade Vol. 182, 1263-1265, October 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.07.075
www.jurology.com
1263
1264
OPPOSING VIEWS
III or higher VUR. Using this approach, the authors concluded that if only those with positive DMSA scans were evaluated with cystography, VCUGs would have been avoided in half their patients. Not only would this reduce the number of children being evaluated with VCUGs, it would also avoid treatment of children with clinically insignificant VUR. It is obvious that the debate regarding the optimal
management of VUR and UTIs continues as it should, since treating every child as if they were a “nail” with one or another therapeutic “hammer” does a disservice to our patients. Hans G. Pohl George Washington University, School of Medicine Children’s National Medical Center Washington, DC
PIC Cystography: An Effective Test for the Diagnosis of Clinically Significant Occult Reflux SINCE the PIC cystogram was introduced more than 5 years ago,5 there has been controversy regarding its potential use in evaluating children with UTIs. Part of this controversy is likely due to a misunderstanding of what the PIC cystogram is and in whom it should be used. Before I make the argument for the clinical usefulness of this study, let’s first look at a case of a typical child in whom a PIC cystogram should be considered. A 6-year-old girl presents with a febrile UTI. She has a normal ultrasound and VCUG. Dysfunctional voiding is diagnosed and treated appropriately but she has 2 recurrent febrile UTIs. This case is not uncommon since up to 50% of children with febrile UTIs will have normal radiographic studies, and some of these children will have recurrent febrile UTIs despite adequate treatment of the dysfunctional voiding. These recurrent infections can be very troublesome to manage. The 2 questions now are 1) why is the patient having recurrent febrile UTIs and 2) what is the next step. Possible reasons for recurrent infections include the presence of host and bacterial virulence factors, as well as inadequately treated dysfunctional elimination. Nevertheless, it is also widely accepted that “occult” reflux may be present which allows for the ascent of a lower tract infection to the upper tracts. If so, identification and treatment of this occult reflux should result in a decrease in recurrent febrile UTIs. The PIC cystogram represents a simple way to identify this type of occult reflux that is clinically significant. The evolution of the PIC cystogram was based on observations that children with febrile UTIs and a negative VCUG were often found to have patulous orifices on cystoscopy which easily hydrodistended. These findings led to supposition that occult reflux was present. Several studies have now been performed to evaluate the validity and usefulness of the PIC cystogram to identify occult reflux. In the first pilot study Rubenstein et al evaluated a control
group of 15 patients with no history of UTIs and a normal VCUG, and a study group of 30 patients with a history of recurrent febrile UTIs and a normal VCUG.5 All patients underwent PIC cystography. PIC revealed no reflux in the control group but was positive for reflux in all 30 patients in the study group. The 0% incidence of PIC positive reflux in the control group is important since this confirms that PIC cystography will not cause reflux in a normal orifice. This observation counters the suggestion that one can make a normal orifice reflux with a PIC cystogram. Subsequently, Edmondson et al performed a follow-up study at 4 separate institutions to ensure that these initial findings were valid and not institution specific.4 They demonstrated that PIC was positive for reflux in more than 80% of patients with febrile UTIs and negative radiographic studies. Following review of these initial studies one may ask the question, so what. Just because a patient has PIC positive reflux does not mean that this reflux is clinically significant. This is a valid and important question to address. To further evaluate whether PIC positive reflux is truly clinically significant, a recent multi-institutional study was performed.10 The hypothesis was straightforward: if this type of reflux is clinically significant (and not just an artifactual radiographic finding), then patients with PIC reflux should have a significant reduction in febrile UTIs when the reflux is surgically treated. The study included 87 patients who had undergone surgical correction of PIC positive reflux (endoscopic 85 and open reimplantation 2). There was a highly statistically significant decrease in the number of febrile UTIs per child per month following surgery. This finding strongly suggests that PIC positive reflux is indeed clinically significant. Those individuals that argue that the PIC cystogram has no place in the evaluation of children with febrile UTIs will point out that there are no significant data to look at the relationship of PIC positive
OPPOSING VIEWS
reflux and renal scarring and that there are other reasons for ascending infections in children. These are valid points. In addition, many have also argued that we should not be looking for occult reflux when we are not even sure if we should be treating low grade reflux in symptomatic children. This may also be true. However, if we attempt to simplify the argument, we can hopefully come to more of a consensus. Thus, if one asks the question, can the PIC cystogram identify clinically significant reflux in patients with recurrent febrile UTIs and a negative VCUG, the preponderance of available data strongly suggests that the answer is yes. More importantly, the majority of patients with PIC positive reflux will benefit clinically by a reduced risk of recurrent febrile UTIs when this occult reflux is surgically corrected. Whether the treatment of PIC positive reflux reduces renal scarring is not the question we are ask-
1265
ing at this time, although it should be evaluated further in additional studies.11 We are simply trying to identify a subset of difficult cases of occult reflux that can be treated with subsequent reduction of the morbidity of future febrile UTIs. Also, one needs to realize that the prevention of renal scarring should not be the sole objective of treating UTIs. It is also our job as urologists to identify and eradicate risk factors that contribute to ascending infections. The ability to identify occult reflux as a causative factor that can be treated surgically and reduce the risk of future UTIs is pleasing and beneficial to patients and their families. Clearly, the PIC cystogram is a valuable test that has great clinical usefulness when used appropriately. Earl Y. Cheng Children’s Memorial Hospital The Feinberg School of Medicine at Northwestern University Chicago, Illinois
REFERENCES 1. Majd M and Rushton HG: Renal cortical scintigraphy in the diagnosis of acute pyelonephritis. Semin Nucl Med 1992; 22: 98. 2. Papadopoulou F, Efremidis SC, Oiconomou A et al: Cyclic voiding cystourethrography: is vesicoureteral reflux missed with standard voiding cystourethrography? Eur Radiol 2002; 12: 666. 3. Paltiel HJ, Rupich RC and Kiruluta HG: Enhanced detection of vesicoureteral reflux in infants and children with use of cyclic voiding cystourethrography. Radiology 1992; 184: 753. 4. Edmondson JD, Maizels M, Alpert SA et al: Multiinstitutional experience with PIC cystography—incidence of occult vesicoureteral reflux in children with febrile urinary tract infections. Urology 2006; 67: 608.
5. Rubenstein JN, Maizels M, Kim SC et al: The PIC cystogram: a novel approach to identify “occult” vesicoureteral reflux in children with febrile urinary tract infections. J Urol 2003; 169: 2339. 6. Cooper CS, Chung BI, Kirsch AJ et al: The outcome of stopping prophylactic antibiotics in older children with vesicoureteral reflux. J Urol 2000; 163: 269. 7. Tseng MH, Lin WJ, Lo WT et al: Does a normal DMSA obviate the performance of voiding cystourethrography in evaluation of young children after their first urinary tract infection? J Pediatr 2007; 150: 96. 8. Hansson S, Dhamey M, Sigstrom O et al: Dimercapto-succinic acid scintigraphy instead of void-
ing cystourethrography for infants with urinary tract infection. J Urol 2004; 172: 1071. 9. Preda I, Jodal U, Sixt R et al: Normal dimercaptosuccinic acid scintigraphy makes voiding cystourethrography unnecessary after urinary tract infection. J Pediatr 2007; 151: 581. 10. Hagerty J, Maizels M, Kirsch A et al: PIC Cystography Group: Treatment of occult reflux lowers the incidence rate of pediatric febrile urinary tract infection. Urology 2008; 72: 72. 11. Tareen BU, Bui D, McMahon DR et al: Role of positional instillation of contrast cystography in the algorithm for evaluating children with confirmed pyelonephritis. Urology 2006; 67: 1055.
PIC Cystography: A Selective Approach to the Diagnosis of Vesicoureteral Reflux WE cannot deny the positive impact that has been made on the incidence of severe acquired renal cortical scarring through the early diagnosis of vesicoureteral reflux (VUR) and the prevention of recurrent acute pyelonephritis (APN) via prophylactic antibiotics and/or surgical intervention as indicated. Proponents of the PIC (positioned instillation of contrast) cystogram advocate its use on the basis that febrile urinary tract infection (UTI) is not associated with VUR in up to 65% of cases evaluated by standard voiding cystourethrography (VCUG) and, thus, the sensitivity of VCUG for the detection of VUR is wanting, and that all VUR should be identified and treated— which is conveniently accomplished under the same anesthetic by endoscopic means. The standard evaluation of febrile UTI in children has long included ultrasonography and VCUG. Using this approach, the prevalence of VUR in children presenting with febrile UTI varies between 25% and 50% (mean 35%) depending on the timing of the VCUG and the number of fill-void cycles performed. Using dimercapto-succinic acid (DMSA) renal scans to document the presence of APN, Majd and Rushton performed a VCUG during hospitalization and found VUR in only 37% of patients with renal cortical abnormalities.1 Other studies have shown that when a VCUG is delayed 4 to 6 weeks following presentation for febrile UTI the diagnosis of VUR will be missed in as many as 28.5% of children. In addition, it has been reported that grades III and higher VUR can be missed in up to a third of patients undergoing only 1 filling cycle, whereas generally 2 filling cycles increase the yield of identifying low to moderate grade VUR.2,3 While it is true that VUR can elude diagnosis depending on the timing and technique used during VCUG, it is illogical to argue that VUR that can only be demonstrated by positioning a stream of contrast at the ureteral orifice is not iatrogenic. Children with presumed PIC positive VUR and uropathogenic bacteria that infect the upper tracts do not have 0022-5347/09/1824-1263/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
the benefit of a cystoscope to gain access to the upper urinary tract. Even so, when PIC cystography is performed the VUR that is identified is generally of low grade and no child is offered the opportunity to undergo long-term followup to assess the impact of maturation and/or intervention for voiding dysfunction before surgery is performed.4,5 Assuming that occult VUR does exist, what is the evidence to support that all VUR, even that which presents with UTI, requires surgical intervention? Cooper et al reported their observations on 51 children whose prophylaxis was discontinued despite persistent VUR.6 During a mean followup of 3.7 years VUR resolved in 19.6% of the children. UTI recurred in 11.8% (6 of 51) of children following cessation of prophylaxis, prompting reimplantation in 5 of the 6 children but in no child was acquired renal cortical scarring documented. Clearly there is a subset of children at risk for recurrent UTI and renal scarring with and without VUR, which should be the focus of intervention, while the majority of children may do well without antibiotics or surgery for VUR. Recently, several studies have advocated the concept of a “top down” approach to the evaluation of children with UTIs.7,8 This selective approach focuses on renal status rather than the presence or absence of VUR. The goal of this approach is to identify only those children with clinically significant VUR, defined as those at risk for renal scarring or recurrent febrile UTIs. It begins with a DMSA scan, reserving evaluation with a VCUG only for those who have abnormal DMSA findings or subsequent recurrent UTIs. This approach is supported by prior clinical studies of abnormal DMSA findings in 80% to 90% of children with VUR and febrile UTIs, including almost all with grade III or higher VUR.7 In a recent prospective study this approach was analyzed in 290 patients (79% with fever 38.5C or greater).9 DMSA scans within 2 weeks of the infection demonstrated abnormalities in 51% of patients, including 96% (26 of 27) of those with grade Vol. 182, 1263-1265, October 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.07.075
www.jurology.com
1263
1264
OPPOSING VIEWS
III or higher VUR. Using this approach, the authors concluded that if only those with positive DMSA scans were evaluated with cystography, VCUGs would have been avoided in half their patients. Not only would this reduce the number of children being evaluated with VCUGs, it would also avoid treatment of children with clinically insignificant VUR. It is obvious that the debate regarding the optimal
management of VUR and UTIs continues as it should, since treating every child as if they were a “nail” with one or another therapeutic “hammer” does a disservice to our patients. Hans G. Pohl George Washington University, School of Medicine Children’s National Medical Center Washington, DC
PIC Cystography: An Effective Test for the Diagnosis of Clinically Significant Occult Reflux SINCE the PIC cystogram was introduced more than 5 years ago,5 there has been controversy regarding its potential use in evaluating children with UTIs. Part of this controversy is likely due to a misunderstanding of what the PIC cystogram is and in whom it should be used. Before I make the argument for the clinical usefulness of this study, let’s first look at a case of a typical child in whom a PIC cystogram should be considered. A 6-year-old girl presents with a febrile UTI. She has a normal ultrasound and VCUG. Dysfunctional voiding is diagnosed and treated appropriately but she has 2 recurrent febrile UTIs. This case is not uncommon since up to 50% of children with febrile UTIs will have normal radiographic studies, and some of these children will have recurrent febrile UTIs despite adequate treatment of the dysfunctional voiding. These recurrent infections can be very troublesome to manage. The 2 questions now are 1) why is the patient having recurrent febrile UTIs and 2) what is the next step. Possible reasons for recurrent infections include the presence of host and bacterial virulence factors, as well as inadequately treated dysfunctional elimination. Nevertheless, it is also widely accepted that “occult” reflux may be present which allows for the ascent of a lower tract infection to the upper tracts. If so, identification and treatment of this occult reflux should result in a decrease in recurrent febrile UTIs. The PIC cystogram represents a simple way to identify this type of occult reflux that is clinically significant. The evolution of the PIC cystogram was based on observations that children with febrile UTIs and a negative VCUG were often found to have patulous orifices on cystoscopy which easily hydrodistended. These findings led to supposition that occult reflux was present. Several studies have now been performed to evaluate the validity and usefulness of the PIC cystogram to identify occult reflux. In the first pilot study Rubenstein et al evaluated a control
group of 15 patients with no history of UTIs and a normal VCUG, and a study group of 30 patients with a history of recurrent febrile UTIs and a normal VCUG.5 All patients underwent PIC cystography. PIC revealed no reflux in the control group but was positive for reflux in all 30 patients in the study group. The 0% incidence of PIC positive reflux in the control group is important since this confirms that PIC cystography will not cause reflux in a normal orifice. This observation counters the suggestion that one can make a normal orifice reflux with a PIC cystogram. Subsequently, Edmondson et al performed a follow-up study at 4 separate institutions to ensure that these initial findings were valid and not institution specific.4 They demonstrated that PIC was positive for reflux in more than 80% of patients with febrile UTIs and negative radiographic studies. Following review of these initial studies one may ask the question, so what. Just because a patient has PIC positive reflux does not mean that this reflux is clinically significant. This is a valid and important question to address. To further evaluate whether PIC positive reflux is truly clinically significant, a recent multi-institutional study was performed.10 The hypothesis was straightforward: if this type of reflux is clinically significant (and not just an artifactual radiographic finding), then patients with PIC reflux should have a significant reduction in febrile UTIs when the reflux is surgically treated. The study included 87 patients who had undergone surgical correction of PIC positive reflux (endoscopic 85 and open reimplantation 2). There was a highly statistically significant decrease in the number of febrile UTIs per child per month following surgery. This finding strongly suggests that PIC positive reflux is indeed clinically significant. Those individuals that argue that the PIC cystogram has no place in the evaluation of children with febrile UTIs will point out that there are no significant data to look at the relationship of PIC positive
OPPOSING VIEWS
reflux and renal scarring and that there are other reasons for ascending infections in children. These are valid points. In addition, many have also argued that we should not be looking for occult reflux when we are not even sure if we should be treating low grade reflux in symptomatic children. This may also be true. However, if we attempt to simplify the argument, we can hopefully come to more of a consensus. Thus, if one asks the question, can the PIC cystogram identify clinically significant reflux in patients with recurrent febrile UTIs and a negative VCUG, the preponderance of available data strongly suggests that the answer is yes. More importantly, the majority of patients with PIC positive reflux will benefit clinically by a reduced risk of recurrent febrile UTIs when this occult reflux is surgically corrected. Whether the treatment of PIC positive reflux reduces renal scarring is not the question we are ask-
1265
ing at this time, although it should be evaluated further in additional studies.11 We are simply trying to identify a subset of difficult cases of occult reflux that can be treated with subsequent reduction of the morbidity of future febrile UTIs. Also, one needs to realize that the prevention of renal scarring should not be the sole objective of treating UTIs. It is also our job as urologists to identify and eradicate risk factors that contribute to ascending infections. The ability to identify occult reflux as a causative factor that can be treated surgically and reduce the risk of future UTIs is pleasing and beneficial to patients and their families. Clearly, the PIC cystogram is a valuable test that has great clinical usefulness when used appropriately. Earl Y. Cheng Children’s Memorial Hospital The Feinberg School of Medicine at Northwestern University Chicago, Illinois
REFERENCES 1. Majd M and Rushton HG: Renal cortical scintigraphy in the diagnosis of acute pyelonephritis. Semin Nucl Med 1992; 22: 98. 2. Papadopoulou F, Efremidis SC, Oiconomou A et al: Cyclic voiding cystourethrography: is vesicoureteral reflux missed with standard voiding cystourethrography? Eur Radiol 2002; 12: 666. 3. Paltiel HJ, Rupich RC and Kiruluta HG: Enhanced detection of vesicoureteral reflux in infants and children with use of cyclic voiding cystourethrography. Radiology 1992; 184: 753. 4. Edmondson JD, Maizels M, Alpert SA et al: Multiinstitutional experience with PIC cystography—incidence of occult vesicoureteral reflux in children with febrile urinary tract infections. Urology 2006; 67: 608.
5. Rubenstein JN, Maizels M, Kim SC et al: The PIC cystogram: a novel approach to identify “occult” vesicoureteral reflux in children with febrile urinary tract infections. J Urol 2003; 169: 2339. 6. Cooper CS, Chung BI, Kirsch AJ et al: The outcome of stopping prophylactic antibiotics in older children with vesicoureteral reflux. J Urol 2000; 163: 269. 7. Tseng MH, Lin WJ, Lo WT et al: Does a normal DMSA obviate the performance of voiding cystourethrography in evaluation of young children after their first urinary tract infection? J Pediatr 2007; 150: 96. 8. Hansson S, Dhamey M, Sigstrom O et al: Dimercapto-succinic acid scintigraphy instead of void-
ing cystourethrography for infants with urinary tract infection. J Urol 2004; 172: 1071. 9. Preda I, Jodal U, Sixt R et al: Normal dimercaptosuccinic acid scintigraphy makes voiding cystourethrography unnecessary after urinary tract infection. J Pediatr 2007; 151: 581. 10. Hagerty J, Maizels M, Kirsch A et al: PIC Cystography Group: Treatment of occult reflux lowers the incidence rate of pediatric febrile urinary tract infection. Urology 2008; 72: 72. 11. Tareen BU, Bui D, McMahon DR et al: Role of positional instillation of contrast cystography in the algorithm for evaluating children with confirmed pyelonephritis. Urology 2006; 67: 1055.