http://informahealthcare.com/sju ISSN: 2168-1805 (print), 2168-1813 (electronic) Scand J Urol, 2015; Early Onlne: 1–5 DOI: 10.3109/21681805.2015.1009485
ORIGINAL ARTICLE
Consequences of following the new American Academy of Pediatrics guidelines for imaging children with urinary tract infection Marko Tapani Ristola 1 and Timo Hurme2 Faculty of Medicine, University of Turku, Turku, Finland, and 2Department of Pediatric Surgery, Turku University Hospital, Turku, Finland
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1
Abstract
Keywords:
Objective.Urinary tract infections (UTIs) and vesicoureteral reflux (VUR) are assumed to predispose children to renal damage. Awareness of the significance of VUR and the possibility of reducing UTI recurrence and renal damage has warranted guidelines on which patients should undergo imaging after UTI. An authoritative guideline has been issued by the American Academy of Pediatrics (AAP). This study assessed the applicability of the AAP guidelines to a subpopulation of patients with UTI, 2–24-month-old children with febrile UTI. Materials and methods. The records of 394 children aged 2–24 months with their first UTI were reviewed. Data were recorded on the indications for renal and bladder ultrasonography (RBUS) and voiding cystourethrography (VCUG) according to the AAP guidelines, RBUS results, VCUG results, use of antimicrobial prophylaxis, antireflux procedures and other urological treatment, and UTI recurrence. Results.An indication for RBUS was seen in 344 patients. RBUS results were abnormal in 87, including 53 with urinary tract dilatation. An unnecessary RBUS would have been avoided in 43 patients. Seven patients with an abnormal RBUS would not have undergone RBUS. An indication for VCUG was seen in 126 patients. VCUG was performed in 206 patients; VUR was found in 72 patients, including 36 with high-grade VUR. An unnecessary VCUG would have been avoided in 82 patients. High-grade VUR would have been missed in six patients. Five patients would not have undergone surgery. Conclusion. The AAP guidelines for imaging studies in children aged 2–24 months with febrile UTI seem applicable to clinical practice.
Diagnostic imaging, guidelines, infant, urinary tract infection, vesicoureteral reflux
Introduction As knowledge on the significance of vesicoureteral reflux (VUR) has increased, several guidelines have been formulated to reduce the number of unnecessary voiding cystourethrography (VCUG) procedures [1–6]. Based largely on a recent meta-analysis [7] in which antimicrobial prophylaxis was found to be of no significant benefit in patients with or without grade 1–4 VUR, the American Academy of Pediatrics (AAP) revised their guidelines in 2011 [8]. While the 1999 guidelines “strongly encouraged” imaging studies after a first urinary tract infection (UTI), the new guidelines recommend imaging studies, especially VCUG, only to a selected subpopulation of patients with risk factors for both VUR and progressive renal damage. Routine use of antimicrobial prophylaxis in patients with VUR is also no longer recommended, as emphasis has shifted to the prompt diagnosis and treatment of UTIs. Compared with the National Institute for Health and Care Excellence (NICE) guidelines [1], the AAP guidelines are similar, although the threshold for recommending renal and bladder ultrasonography (RBUS) and VCUG is slightly lower in children aged 6–24 months. The present authors recently conducted a study involving 672 patients on the applicability of the NICE guidelines, and
History Received 23 October 2014 Revised 12 January 2015 Accepted 13 January 2015
recommended against the use of the NICE guidelines for imaging studies in children under the age of 3 years [9]. This recommendation was based on the fact that a significant number of children with high-grade VUR and whose imaging studies led to surgery would have been missed had the NICE guidelines been applied. In this retrospective study, the AAP guidelines were evaluated using similar methods, but focusing on children aged 2–24 months with febrile UTI. Two similar studies [10,11] have been published, but the results are inconclusive.
Materials and methods The records of 394 patients aged 2–24 months treated for UTI in the University Hospital of Turku between 1 January 2000 and 31 December 2009 were reviewed. There were 147 boys and 247 girls. The exclusion criteria were: previously diagnosed urological abnormalities (e.g. hydronephrosis in antenatal ultrasound), any neurological or anatomical abnormalities known to be associated with recurrent UTIs or renal damage, no RBUS, and having had the imaging studies performed in another healthcare district or moving to another healthcare district before the imaging studies.
Correspondence: Marko Tapani Ristola, Sukkulakuja 3 B 30, 20100 Turku, Finland. Tel: +358 50 550 5654. E-mail: [email protected] Informa Healthcare.
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2 M. T. Ristola & T. Hurme All patients’ antenatal ultrasonography results were reviewed, and all patients were found to have normal urinary systems. The diagnosis of UTI was considered “certain” if there were both urinalysis results compatible with infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colony-forming units of bacteria per milliliter (cfu/ml). Catheter samples were not used. Suprapubic aspiration (SPA) was often unsuccessfully attempted; hence, a large proportion of the diagnoses was based on bag specimens. Fever was defined as per AAP guidelines as a body temperature of at least 38.0 C (100.4 F) [8]. Antimicrobial treatment followed national routine procedures in the department. The antibiotic drug was determined according to the antibiogram of the uropathogen in each case. If antibiotic treatment was started before the antibiogram was available, the drug of choice for pyelonephritis was intravenous cefuroxime and for cystitis an oral antibiotic agent, occasionally preceded by a single intramuscular injection of ceftriaxone. Most patients with pyelonephritis received intravenous cefuroxime for 3 days followed by an oral antibiotic after discharge from the hospital for a total treatment period of 10 days. The most common oral antibiotics were trimethoprim–sulfamethoxazole, amoxicillin–clavulanic acid and cefalexine. All patients in the cohort underwent RBUS. Selected patients (based on the judgment of the clinician in each case) also underwent VCUG, dimercaptosuccinic acid (DMSA) renal scintigraphy or mercaptoacetyltriglycine (MAG3) renal scanning to identify VUR, renal parenchymal damage or urinary tract obstruction, respectively. Where possible, the VUR of all patients was graded according to the International Reflux Study in Children [12] criteria, and the highest grade of all studies was recorded for this study. The common finding in nuclear VCUG, “VUR reaching the level of the kidney”, with no reference to dilatation, was defined as grade 2. However, data regarding dilatation in RBUS were combined with the nuclear VCUG finding to determine the grade of VUR as accurately as possible. In bilateral VUR, the higher grade was used for classification. The indications for RBUS and VCUG were in concordance with the AAP guidelines. Confirmed febrile UTI was an indication for RBUS. Indications for VCUG were hydronephrosis, renal scarring and other findings in RBUS suggestive of high-grade VUR or obstructive uropathy, recurrent febrile UTI, or other atypical or complex situations (see Discussion). Patients were followed up for a mean of 8.1 years (range 3.9–13.9 years). Data were collected on UTI recurrence, use of antimicrobial prophylaxis, imaging studies, antireflux surgery and other urological procedures. An evaluation was made of how the patients’ diagnoses and treatment would have changed had the AAP guidelines been applied to clinical practice in this cohort. Statistical comparisons between any two groups were made with Fisher’s exact test; p < 0.05 was considered statistically significant.
Results All patients underwent RBUS. Of the 394 patients with their first confirmed UTI, 344 had a febrile UTI and RBUS was
Scand J Urol, 2015; Early Online: 1–5
Table 1. Data on 394 children with their first urinary tract infection. Group
Boys
Girls
All patients
Total number of patients Indication for RBUS RBUS performed Abnormal RBUS Dilatation Hydronephrosis Mild pelvic or ureteral dilatation Renal scarring Abnormal kidney size Duplicated ureter Ureterocele Nephrocalcinosis Bladder cyst Paraureteral diverticulum Urachal cyst Kidney stone Laterally positioned ureterovesical junction Indication for VCUG VCUG performed VUR on VCUG Low-grade VUR High-grade VUR Antimicrobial prophylaxis for VURa Surgery Endoscopic injection treatmentb Ureteroneocystostomy Nephrectomy Pyeloplasty Excision of ureterocele Circumcision Nephrostomy
147 119 147 38 22 11 11 9 10 3 2 1 0 1 0 0 0
247 225 247 49 31 9 22 12 14 10 1 1 1 0 1 1 1
394 344 394 87 53 20 33 21 24 13 3 2 1 1 1 1 1
52 86 33 17 16 27 16 5 2 2 3 2 1 1
74 120 39 19 20 33 18 15 2 0 1 1 0 0
126 206 72 36 36 60 34 20 4 2 4 3 1 1
a
Twenty-six of the 60 patients were prescribed antimicrobial prophylaxis despite being diagnosed with only low-grade VUR. b One of the 20 patients underwent endoscopic injection treatment despite being diagnosed with only low-grade VUR. RBUS = renal and bladder ultrasonography; VCUG = voiding cystourethrography; VUR = vesicoureteral reflux.
indicated according to AAP guidelines (Table 1). Fifty patients underwent RBUS although it was not indicated. Two of these patients had a febrile UTI later, before 24 months of age, and would have then had an indication for RBUS. RBUS results were abnormal in 87 patients (22%), including 53 patients (13%) with dilatation of the urinary tract (Table 1). Of the 50 patients who underwent RBUS although it was not indicated, seven (14%) had abnormal findings, including five (10%) with dilatation of the urinary tract (Table 2). Two patients fulfilled the RBUS indications criteria later on during follow-up, and both had normal RBUS findings; one of them also underwent VCUG where no VUR was found. An abnormal RBUS without an indication led to surgery in only one patient (pyeloplasty for obstruction of the pyeloureteral junction). RBUS would have been avoided in 43 patients (14%) with normal findings (Table 2). VCUG was indicated for 126 patients (32%), of whom 100 underwent a VCUG (Table 1). Altogether, 206 patients (52%) underwent VCUG. Seventy-three patients underwent only standard VCUG and 107 only nuclear VCUG, 25 patients underwent both, and one patient underwent indirect radionuclide cystography. VUR was found in 72 patients (35%), including 36 (17%) with high-grade VUR. Of the
AAP guidelines on imaging children with UTI
DOI: 10.3109/21681805.2015.1009485
Table 2. Clinical consequences of applying the American Academy of Pediatrics guidelines in 394 children with their first urinary tract infection.
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Group RBUS avoided in patients with normal RBUS findings Abnormal RBUS not performed Hydronephrosis not found Mild dilatation not found Renal scarring not found Duplicated ureter not found Nephrocalcinosis not found VCUG avoided in patients with no VUR VUR on VCUG not found Low-grade VUR not found High-grade VUR not found Antimicrobial prophylaxis for VUR not assigneda Surgery not performed Endoscopic injection treatment for VUR not performedb Pyeloplasty not performed
Boys Girls All patients 22
21
43
6 1 3 2 2 0 38 12 10 2 9
1 0 1 0 0 1 44 12 8 4 7
7 1 4 2 2 1 82 24 18 6 16
2 1
3 3
5 4
1
0
1
a
Eleven of the 16 patients were prescribed antimicrobial prophylaxis despite being diagnosed with only low-grade VUR. bOne of the three girls underwent endoscopic injection treatment despite being diagnosed with only low-grade VUR. RBUS = renal and bladder ultrasonography; VCUG = voiding cystourethrography; VUR = vesicoureteral reflux.
106 patients who underwent VCUG without an indication, 24 (23%) had VUR. These included six (5.7%) with highgrade VUR. One of these patients had a recurrent febrile UTI before the age of 24 months, which would have indicated VCUG. Patients for whom VCUG was indicated were more likely to have both VUR (p = 0.0001) and high-grade VUR (p < 0.0001). VCUG would have been avoided in 82 of the 134 patients (61%) with no VUR in VCUG (Tables 1 and 2). Altogether, 32 patients (8.1%) had a confirmed UTI recurrence during follow-up. Of these patients, 28 (88%) underwent a VCUG and 21 (75%) were diagnosed with VUR, including 15 patients (54%) with high-grade VUR. Antimicrobial prophylaxis for VUR was prescribed for 60 patients (Table 1), 16 (27%) of whom did not have an indication for VCUG (Table 2); 11 of these 16 patients (69%) had only low-grade VUR. Thirty-four patients underwent surgery owing to abnormal findings after a first episode of UTI: 20 patients underwent endoscopic injection treatment for VUR and four underwent ureteroneocystostomy (UNC), only one of whom underwent UNC for VUR (Table 1). Of the 20 patients who underwent endoscopic injection treatment for VUR, four did not have an indication for VCUG. However, one of them had only low-grade VUR. In addition, one patient who underwent pyeloplasty did not have an indication for any imaging studies (Table 2).
Discussion Of the 36 patients who had high-grade VUR, six (17%) would have been missed if the AAP guidelines had been applied. In addition, five patients (15%) would not have undergone surgical treatment or it would have been delayed.
3
The benefit of following the AAP guidelines would have been avoiding performing RBUS in 43 patients (14%) with normal findings, and avoiding performing VCUG in 82 patients (61%) with normal findings. The AAP guidelines state that VCUG is also indicated “in other atypical or complex situations”, leaving room for interpretation. For the purposes of this study, the following were defined as being “atypical or complex situations”: infection with a non-Escherichia coli organism, septicemia, elevated serum creatinine concentration, failure to respond to appropriate antibiotics in 48 h, poor urine flow or a family history of VUR. There were 67 patients who fell into this category, and VCUG was performed on 47 of these patients, 24 of whom (51%) had VUR, including 11 (23%) with high-grade VUR. All of these 11 patients had some other indication for VCUG besides the “atypical or complex situation”. None of the 25 patients whose only indication for VCUG was “other atypical or complex situation” underwent surgery. In other words, no high-grade VUR or other findings requiring surgical treatment would have been missed, even if VCUG had not been performed in these “atypical or complex” situations. Two studies have been published on the clinical applicability of the AAP guidelines. In a retrospective cohort study of 174 patients aged 2–24 months with pyelonephritis, Juliano et al. [10] reported that 24% of patients had dilating VUR despite a normal RBUS. Seven percent of patients with a normal RBUS underwent surgical intervention for persistent VUR. Suson and Mathews [11] evaluated retrospectively a cohort of 49 patients (42 girls) with VUR after a febrile UTI, and found that 62.1% of the patients with normal RBUS findings had dilating VUR. The number of patients in this study was relatively small, and the authors did not evaluate “atypical or complex situations” which are also indications for VCUG by the AAP guidelines. In addition, one study [13] stated that implementation of the AAP guidelines resulted in a substantial decrease in the rate of VCUGs in children with first UTI and normal RBUS, both among those hospitalized (from 92% to 0%) and among those treated in the emergency department (from 100% to 40%). While the AAP guidelines recommend that all children undergo RBUS after a febrile UTI, Sasaki et al. [14] stated that a post-UTI RBUS may not be needed in children under the age of 1 year with a normal antenatal ultrasonogram. This was based on the fact that only 5.1% of the patients in their cohort with normal antenatal ultrasonograms had abnormal RBUS findings after a first UTI. Other studies [15–17] found the rate of abnormal RBUS after a first UTI to be higher, from 12% to 14.1%. Of the 394 patients with normal antenatal ultrasonograms in the present cohort, 87 (22%) had abnormal RBUS findings after a UTI. These included 53 patients (13%) with dilatation of the urinary tract. Therefore, RBUS in children after a febrile UTI is justified as, at least in this institution, the accuracy of antenatal ultrasonography seems to be insufficient to identify all patients who will have abnormal RBUS findings after a UTI. The AAP guidelines promote RBUS for all febrile UTI patients. Bearing in mind that VUR and recurrent UTIs are considered to be most harmful in the presence of other urinary tract abnormalities and that RBUS is a non-invasive imaging study without radiation exposure, RBUS for all febrile infants and small children with confirmed UTI is reasonable.
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4 M. T. Ristola & T. Hurme By applying the AAP guidelines, 82 unnecessary VCUGs would have been avoided at the cost of missing six patients with high-grade VUR. At least low-grade VUR is no longer considered a significant finding in children [18], and it is not thought to lead to renal problems later in life; thus, missing a diagnosis of low-grade VUR for 18 patients may be of little significance. There is little evidence suggesting that recurrent UTIs lead to chronic kidney disease in the absence of structural kidney abnormalities, even in the presence of VUR [19]. It has also been shown that VUR is not a prerequisite for renal damage [20–22]. Garin et al. [23] found that children with grade 1–3 VUR are at no greater risk for recurrent UTIs than children without VUR and that antimicrobial prophylaxis is not associated with any statistically significant decrease in the rate of UTI recurrence or new renal scarring in patients with or without grade 1–3 VUR. The consensus among pediatric urologists has indeed shifted towards low-grade VUR not being a significant finding in children with otherwise healthy kidneys. Some pediatric urologists [18] consider even high-grade VUR to be a benign phenomenon that will resolve over time and that requires neither treatment nor active search. Existing data suggest, nevertheless, that, despite the fact that high-grade VUR often resolves spontaneously over a period of months or years, children with highgrade VUR after a febrile UTI benefit from active treatment, and VUR should be actively sought, at least in some patients with febrile UTI [24,25]. AAP does not advise against imaging studies in UTI patients without fever per se, but limits the guideline to febrile infants and children. By analogy, this might be considered to imply that infants and small children with UTI and no fever should not undergo any imaging. In this study, seven out of the 50 patients without fever who underwent RBUS had abnormal findings, including five with dilatation of the urinary tract. If all UTI patients, even those without fever, had undergone RBUS, 43 more patients with normal findings would have undergone RBUS, and two of the six patients whose high-grade VUR diagnoses were missed would have undergone VCUG. Thus, only four patients with high-grade VUR would ultimately have been missed. Based on the results obtained from this cohort, however, it is not possible to evaluate the number of unnecessary RBUS studies that this would lead to, because there is a substantial population of young children, especially girls, whose UTIs without fever are treated outside the hospital. The rationale behind limiting imaging studies so drastically was a meta-analysis [7] on the effectiveness of antimicrobial prophylaxis in patients without VUR or with grade 1–4 VUR. It was found that antimicrobial prophylaxis provides no statistically significant benefit in terms of reduced UTI recurrence or the development of new renal scars compared to no treatment. This meta-analysis has been criticized [26] for not differentiating between girls and boys, although a recent prospective study [24] found that girls with grade 3–4 VUR benefit from antimicrobial prophylaxis, which reduces the rate of febrile UTI recurrence and new renal scarring, and that endoscopic injection treatment reduces the rate of febrile UTI recurrence in girls, while boys do not benefit from either treatment. In the present study, only four of the
Scand J Urol, 2015; Early Online: 1–5
20 girls with high-grade VUR would have been missed (failure rate 20%). In the boys’ group, two of the 16 boys with high-grade VUR would have been missed (failure rate only 13%). This report carries the weaknesses of a retrospective study. The reliability of the initial diagnosis of UTI may be questionable in some cases owing to bag urine specimens after unsuccessful attempts at SPA. Blood bacterial cultures and creatinine values were taken relatively seldom, and performing them more frequently may have resulted in more patients fulfilling the criteria of VCUG. Only 52% of patients in the cohort underwent VCUG. In the Materials and Methods section, it was mentioned that data regarding dilatation in RBUS were combined with the nuclear VCUG finding to determine the grade of VUR as accurately as possible. However, only one patient in this cohort with high-grade VUR was diagnosed based on a positive nuclear VCUG and pelvic dilatation in RBUS. All other patients who were categorized as having high-grade VUR had at least one VCUG showing high-grade VUR. The rate and predisposing factors of UTI recurrence in this cohort are difficult to evaluate. Some patients may have had UTI recurrences diagnosed and treated in another center. In addition, several patients were prescribed antimicrobial prophylaxis, which further complicates the analysis of patterns of UTI recurrence. However, 15 of the 28 patients (54%) who both underwent a VCUG and had a UTI recurrence also had high-grade VUR. Very few patients underwent follow-up imaging to identify renal scars or functional renal impairment, which may be of far greater significance than VUR status. In conclusion, the AAP guidelines seem justifiable for imaging studies in children aged 2–24 months with febrile UTI. The most important argument supporting this conclusion is that very few patients with actionable findings would have been missed had the guidelines been applied, while a significant number of unnecessary VCUGs would have been avoided. Based on this retrospective study, however, the guidelines cannot be conclusively recommended, as a larger, prospective study is needed to determine the true effectiveness of the guidelines. Acknowledgement Dr Robert Paul provided assistance with language and grammar. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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AAP guidelines on imaging children with UTI
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ORIGINAL ARTICLE
Consequences of following the new American Academy of Pediatrics guidelines for imaging children with urinary tract infection Marko Tapani Ristola 1 and Timo Hurme2 Faculty of Medicine, University of Turku, Turku, Finland, and 2Department of Pediatric Surgery, Turku University Hospital, Turku, Finland
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1
Abstract
Keywords:
Objective.Urinary tract infections (UTIs) and vesicoureteral reflux (VUR) are assumed to predispose children to renal damage. Awareness of the significance of VUR and the possibility of reducing UTI recurrence and renal damage has warranted guidelines on which patients should undergo imaging after UTI. An authoritative guideline has been issued by the American Academy of Pediatrics (AAP). This study assessed the applicability of the AAP guidelines to a subpopulation of patients with UTI, 2–24-month-old children with febrile UTI. Materials and methods. The records of 394 children aged 2–24 months with their first UTI were reviewed. Data were recorded on the indications for renal and bladder ultrasonography (RBUS) and voiding cystourethrography (VCUG) according to the AAP guidelines, RBUS results, VCUG results, use of antimicrobial prophylaxis, antireflux procedures and other urological treatment, and UTI recurrence. Results.An indication for RBUS was seen in 344 patients. RBUS results were abnormal in 87, including 53 with urinary tract dilatation. An unnecessary RBUS would have been avoided in 43 patients. Seven patients with an abnormal RBUS would not have undergone RBUS. An indication for VCUG was seen in 126 patients. VCUG was performed in 206 patients; VUR was found in 72 patients, including 36 with high-grade VUR. An unnecessary VCUG would have been avoided in 82 patients. High-grade VUR would have been missed in six patients. Five patients would not have undergone surgery. Conclusion. The AAP guidelines for imaging studies in children aged 2–24 months with febrile UTI seem applicable to clinical practice.
Diagnostic imaging, guidelines, infant, urinary tract infection, vesicoureteral reflux
Introduction As knowledge on the significance of vesicoureteral reflux (VUR) has increased, several guidelines have been formulated to reduce the number of unnecessary voiding cystourethrography (VCUG) procedures [1–6]. Based largely on a recent meta-analysis [7] in which antimicrobial prophylaxis was found to be of no significant benefit in patients with or without grade 1–4 VUR, the American Academy of Pediatrics (AAP) revised their guidelines in 2011 [8]. While the 1999 guidelines “strongly encouraged” imaging studies after a first urinary tract infection (UTI), the new guidelines recommend imaging studies, especially VCUG, only to a selected subpopulation of patients with risk factors for both VUR and progressive renal damage. Routine use of antimicrobial prophylaxis in patients with VUR is also no longer recommended, as emphasis has shifted to the prompt diagnosis and treatment of UTIs. Compared with the National Institute for Health and Care Excellence (NICE) guidelines [1], the AAP guidelines are similar, although the threshold for recommending renal and bladder ultrasonography (RBUS) and VCUG is slightly lower in children aged 6–24 months. The present authors recently conducted a study involving 672 patients on the applicability of the NICE guidelines, and
History Received 23 October 2014 Revised 12 January 2015 Accepted 13 January 2015
recommended against the use of the NICE guidelines for imaging studies in children under the age of 3 years [9]. This recommendation was based on the fact that a significant number of children with high-grade VUR and whose imaging studies led to surgery would have been missed had the NICE guidelines been applied. In this retrospective study, the AAP guidelines were evaluated using similar methods, but focusing on children aged 2–24 months with febrile UTI. Two similar studies [10,11] have been published, but the results are inconclusive.
Materials and methods The records of 394 patients aged 2–24 months treated for UTI in the University Hospital of Turku between 1 January 2000 and 31 December 2009 were reviewed. There were 147 boys and 247 girls. The exclusion criteria were: previously diagnosed urological abnormalities (e.g. hydronephrosis in antenatal ultrasound), any neurological or anatomical abnormalities known to be associated with recurrent UTIs or renal damage, no RBUS, and having had the imaging studies performed in another healthcare district or moving to another healthcare district before the imaging studies.
Correspondence: Marko Tapani Ristola, Sukkulakuja 3 B 30, 20100 Turku, Finland. Tel: +358 50 550 5654. E-mail: [email protected] Informa Healthcare.
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2 M. T. Ristola & T. Hurme All patients’ antenatal ultrasonography results were reviewed, and all patients were found to have normal urinary systems. The diagnosis of UTI was considered “certain” if there were both urinalysis results compatible with infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colony-forming units of bacteria per milliliter (cfu/ml). Catheter samples were not used. Suprapubic aspiration (SPA) was often unsuccessfully attempted; hence, a large proportion of the diagnoses was based on bag specimens. Fever was defined as per AAP guidelines as a body temperature of at least 38.0 C (100.4 F) [8]. Antimicrobial treatment followed national routine procedures in the department. The antibiotic drug was determined according to the antibiogram of the uropathogen in each case. If antibiotic treatment was started before the antibiogram was available, the drug of choice for pyelonephritis was intravenous cefuroxime and for cystitis an oral antibiotic agent, occasionally preceded by a single intramuscular injection of ceftriaxone. Most patients with pyelonephritis received intravenous cefuroxime for 3 days followed by an oral antibiotic after discharge from the hospital for a total treatment period of 10 days. The most common oral antibiotics were trimethoprim–sulfamethoxazole, amoxicillin–clavulanic acid and cefalexine. All patients in the cohort underwent RBUS. Selected patients (based on the judgment of the clinician in each case) also underwent VCUG, dimercaptosuccinic acid (DMSA) renal scintigraphy or mercaptoacetyltriglycine (MAG3) renal scanning to identify VUR, renal parenchymal damage or urinary tract obstruction, respectively. Where possible, the VUR of all patients was graded according to the International Reflux Study in Children [12] criteria, and the highest grade of all studies was recorded for this study. The common finding in nuclear VCUG, “VUR reaching the level of the kidney”, with no reference to dilatation, was defined as grade 2. However, data regarding dilatation in RBUS were combined with the nuclear VCUG finding to determine the grade of VUR as accurately as possible. In bilateral VUR, the higher grade was used for classification. The indications for RBUS and VCUG were in concordance with the AAP guidelines. Confirmed febrile UTI was an indication for RBUS. Indications for VCUG were hydronephrosis, renal scarring and other findings in RBUS suggestive of high-grade VUR or obstructive uropathy, recurrent febrile UTI, or other atypical or complex situations (see Discussion). Patients were followed up for a mean of 8.1 years (range 3.9–13.9 years). Data were collected on UTI recurrence, use of antimicrobial prophylaxis, imaging studies, antireflux surgery and other urological procedures. An evaluation was made of how the patients’ diagnoses and treatment would have changed had the AAP guidelines been applied to clinical practice in this cohort. Statistical comparisons between any two groups were made with Fisher’s exact test; p < 0.05 was considered statistically significant.
Results All patients underwent RBUS. Of the 394 patients with their first confirmed UTI, 344 had a febrile UTI and RBUS was
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Table 1. Data on 394 children with their first urinary tract infection. Group
Boys
Girls
All patients
Total number of patients Indication for RBUS RBUS performed Abnormal RBUS Dilatation Hydronephrosis Mild pelvic or ureteral dilatation Renal scarring Abnormal kidney size Duplicated ureter Ureterocele Nephrocalcinosis Bladder cyst Paraureteral diverticulum Urachal cyst Kidney stone Laterally positioned ureterovesical junction Indication for VCUG VCUG performed VUR on VCUG Low-grade VUR High-grade VUR Antimicrobial prophylaxis for VURa Surgery Endoscopic injection treatmentb Ureteroneocystostomy Nephrectomy Pyeloplasty Excision of ureterocele Circumcision Nephrostomy
147 119 147 38 22 11 11 9 10 3 2 1 0 1 0 0 0
247 225 247 49 31 9 22 12 14 10 1 1 1 0 1 1 1
394 344 394 87 53 20 33 21 24 13 3 2 1 1 1 1 1
52 86 33 17 16 27 16 5 2 2 3 2 1 1
74 120 39 19 20 33 18 15 2 0 1 1 0 0
126 206 72 36 36 60 34 20 4 2 4 3 1 1
a
Twenty-six of the 60 patients were prescribed antimicrobial prophylaxis despite being diagnosed with only low-grade VUR. b One of the 20 patients underwent endoscopic injection treatment despite being diagnosed with only low-grade VUR. RBUS = renal and bladder ultrasonography; VCUG = voiding cystourethrography; VUR = vesicoureteral reflux.
indicated according to AAP guidelines (Table 1). Fifty patients underwent RBUS although it was not indicated. Two of these patients had a febrile UTI later, before 24 months of age, and would have then had an indication for RBUS. RBUS results were abnormal in 87 patients (22%), including 53 patients (13%) with dilatation of the urinary tract (Table 1). Of the 50 patients who underwent RBUS although it was not indicated, seven (14%) had abnormal findings, including five (10%) with dilatation of the urinary tract (Table 2). Two patients fulfilled the RBUS indications criteria later on during follow-up, and both had normal RBUS findings; one of them also underwent VCUG where no VUR was found. An abnormal RBUS without an indication led to surgery in only one patient (pyeloplasty for obstruction of the pyeloureteral junction). RBUS would have been avoided in 43 patients (14%) with normal findings (Table 2). VCUG was indicated for 126 patients (32%), of whom 100 underwent a VCUG (Table 1). Altogether, 206 patients (52%) underwent VCUG. Seventy-three patients underwent only standard VCUG and 107 only nuclear VCUG, 25 patients underwent both, and one patient underwent indirect radionuclide cystography. VUR was found in 72 patients (35%), including 36 (17%) with high-grade VUR. Of the
AAP guidelines on imaging children with UTI
DOI: 10.3109/21681805.2015.1009485
Table 2. Clinical consequences of applying the American Academy of Pediatrics guidelines in 394 children with their first urinary tract infection.
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Group RBUS avoided in patients with normal RBUS findings Abnormal RBUS not performed Hydronephrosis not found Mild dilatation not found Renal scarring not found Duplicated ureter not found Nephrocalcinosis not found VCUG avoided in patients with no VUR VUR on VCUG not found Low-grade VUR not found High-grade VUR not found Antimicrobial prophylaxis for VUR not assigneda Surgery not performed Endoscopic injection treatment for VUR not performedb Pyeloplasty not performed
Boys Girls All patients 22
21
43
6 1 3 2 2 0 38 12 10 2 9
1 0 1 0 0 1 44 12 8 4 7
7 1 4 2 2 1 82 24 18 6 16
2 1
3 3
5 4
1
0
1
a
Eleven of the 16 patients were prescribed antimicrobial prophylaxis despite being diagnosed with only low-grade VUR. bOne of the three girls underwent endoscopic injection treatment despite being diagnosed with only low-grade VUR. RBUS = renal and bladder ultrasonography; VCUG = voiding cystourethrography; VUR = vesicoureteral reflux.
106 patients who underwent VCUG without an indication, 24 (23%) had VUR. These included six (5.7%) with highgrade VUR. One of these patients had a recurrent febrile UTI before the age of 24 months, which would have indicated VCUG. Patients for whom VCUG was indicated were more likely to have both VUR (p = 0.0001) and high-grade VUR (p < 0.0001). VCUG would have been avoided in 82 of the 134 patients (61%) with no VUR in VCUG (Tables 1 and 2). Altogether, 32 patients (8.1%) had a confirmed UTI recurrence during follow-up. Of these patients, 28 (88%) underwent a VCUG and 21 (75%) were diagnosed with VUR, including 15 patients (54%) with high-grade VUR. Antimicrobial prophylaxis for VUR was prescribed for 60 patients (Table 1), 16 (27%) of whom did not have an indication for VCUG (Table 2); 11 of these 16 patients (69%) had only low-grade VUR. Thirty-four patients underwent surgery owing to abnormal findings after a first episode of UTI: 20 patients underwent endoscopic injection treatment for VUR and four underwent ureteroneocystostomy (UNC), only one of whom underwent UNC for VUR (Table 1). Of the 20 patients who underwent endoscopic injection treatment for VUR, four did not have an indication for VCUG. However, one of them had only low-grade VUR. In addition, one patient who underwent pyeloplasty did not have an indication for any imaging studies (Table 2).
Discussion Of the 36 patients who had high-grade VUR, six (17%) would have been missed if the AAP guidelines had been applied. In addition, five patients (15%) would not have undergone surgical treatment or it would have been delayed.
3
The benefit of following the AAP guidelines would have been avoiding performing RBUS in 43 patients (14%) with normal findings, and avoiding performing VCUG in 82 patients (61%) with normal findings. The AAP guidelines state that VCUG is also indicated “in other atypical or complex situations”, leaving room for interpretation. For the purposes of this study, the following were defined as being “atypical or complex situations”: infection with a non-Escherichia coli organism, septicemia, elevated serum creatinine concentration, failure to respond to appropriate antibiotics in 48 h, poor urine flow or a family history of VUR. There were 67 patients who fell into this category, and VCUG was performed on 47 of these patients, 24 of whom (51%) had VUR, including 11 (23%) with high-grade VUR. All of these 11 patients had some other indication for VCUG besides the “atypical or complex situation”. None of the 25 patients whose only indication for VCUG was “other atypical or complex situation” underwent surgery. In other words, no high-grade VUR or other findings requiring surgical treatment would have been missed, even if VCUG had not been performed in these “atypical or complex” situations. Two studies have been published on the clinical applicability of the AAP guidelines. In a retrospective cohort study of 174 patients aged 2–24 months with pyelonephritis, Juliano et al. [10] reported that 24% of patients had dilating VUR despite a normal RBUS. Seven percent of patients with a normal RBUS underwent surgical intervention for persistent VUR. Suson and Mathews [11] evaluated retrospectively a cohort of 49 patients (42 girls) with VUR after a febrile UTI, and found that 62.1% of the patients with normal RBUS findings had dilating VUR. The number of patients in this study was relatively small, and the authors did not evaluate “atypical or complex situations” which are also indications for VCUG by the AAP guidelines. In addition, one study [13] stated that implementation of the AAP guidelines resulted in a substantial decrease in the rate of VCUGs in children with first UTI and normal RBUS, both among those hospitalized (from 92% to 0%) and among those treated in the emergency department (from 100% to 40%). While the AAP guidelines recommend that all children undergo RBUS after a febrile UTI, Sasaki et al. [14] stated that a post-UTI RBUS may not be needed in children under the age of 1 year with a normal antenatal ultrasonogram. This was based on the fact that only 5.1% of the patients in their cohort with normal antenatal ultrasonograms had abnormal RBUS findings after a first UTI. Other studies [15–17] found the rate of abnormal RBUS after a first UTI to be higher, from 12% to 14.1%. Of the 394 patients with normal antenatal ultrasonograms in the present cohort, 87 (22%) had abnormal RBUS findings after a UTI. These included 53 patients (13%) with dilatation of the urinary tract. Therefore, RBUS in children after a febrile UTI is justified as, at least in this institution, the accuracy of antenatal ultrasonography seems to be insufficient to identify all patients who will have abnormal RBUS findings after a UTI. The AAP guidelines promote RBUS for all febrile UTI patients. Bearing in mind that VUR and recurrent UTIs are considered to be most harmful in the presence of other urinary tract abnormalities and that RBUS is a non-invasive imaging study without radiation exposure, RBUS for all febrile infants and small children with confirmed UTI is reasonable.
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4 M. T. Ristola & T. Hurme By applying the AAP guidelines, 82 unnecessary VCUGs would have been avoided at the cost of missing six patients with high-grade VUR. At least low-grade VUR is no longer considered a significant finding in children [18], and it is not thought to lead to renal problems later in life; thus, missing a diagnosis of low-grade VUR for 18 patients may be of little significance. There is little evidence suggesting that recurrent UTIs lead to chronic kidney disease in the absence of structural kidney abnormalities, even in the presence of VUR [19]. It has also been shown that VUR is not a prerequisite for renal damage [20–22]. Garin et al. [23] found that children with grade 1–3 VUR are at no greater risk for recurrent UTIs than children without VUR and that antimicrobial prophylaxis is not associated with any statistically significant decrease in the rate of UTI recurrence or new renal scarring in patients with or without grade 1–3 VUR. The consensus among pediatric urologists has indeed shifted towards low-grade VUR not being a significant finding in children with otherwise healthy kidneys. Some pediatric urologists [18] consider even high-grade VUR to be a benign phenomenon that will resolve over time and that requires neither treatment nor active search. Existing data suggest, nevertheless, that, despite the fact that high-grade VUR often resolves spontaneously over a period of months or years, children with highgrade VUR after a febrile UTI benefit from active treatment, and VUR should be actively sought, at least in some patients with febrile UTI [24,25]. AAP does not advise against imaging studies in UTI patients without fever per se, but limits the guideline to febrile infants and children. By analogy, this might be considered to imply that infants and small children with UTI and no fever should not undergo any imaging. In this study, seven out of the 50 patients without fever who underwent RBUS had abnormal findings, including five with dilatation of the urinary tract. If all UTI patients, even those without fever, had undergone RBUS, 43 more patients with normal findings would have undergone RBUS, and two of the six patients whose high-grade VUR diagnoses were missed would have undergone VCUG. Thus, only four patients with high-grade VUR would ultimately have been missed. Based on the results obtained from this cohort, however, it is not possible to evaluate the number of unnecessary RBUS studies that this would lead to, because there is a substantial population of young children, especially girls, whose UTIs without fever are treated outside the hospital. The rationale behind limiting imaging studies so drastically was a meta-analysis [7] on the effectiveness of antimicrobial prophylaxis in patients without VUR or with grade 1–4 VUR. It was found that antimicrobial prophylaxis provides no statistically significant benefit in terms of reduced UTI recurrence or the development of new renal scars compared to no treatment. This meta-analysis has been criticized [26] for not differentiating between girls and boys, although a recent prospective study [24] found that girls with grade 3–4 VUR benefit from antimicrobial prophylaxis, which reduces the rate of febrile UTI recurrence and new renal scarring, and that endoscopic injection treatment reduces the rate of febrile UTI recurrence in girls, while boys do not benefit from either treatment. In the present study, only four of the
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20 girls with high-grade VUR would have been missed (failure rate 20%). In the boys’ group, two of the 16 boys with high-grade VUR would have been missed (failure rate only 13%). This report carries the weaknesses of a retrospective study. The reliability of the initial diagnosis of UTI may be questionable in some cases owing to bag urine specimens after unsuccessful attempts at SPA. Blood bacterial cultures and creatinine values were taken relatively seldom, and performing them more frequently may have resulted in more patients fulfilling the criteria of VCUG. Only 52% of patients in the cohort underwent VCUG. In the Materials and Methods section, it was mentioned that data regarding dilatation in RBUS were combined with the nuclear VCUG finding to determine the grade of VUR as accurately as possible. However, only one patient in this cohort with high-grade VUR was diagnosed based on a positive nuclear VCUG and pelvic dilatation in RBUS. All other patients who were categorized as having high-grade VUR had at least one VCUG showing high-grade VUR. The rate and predisposing factors of UTI recurrence in this cohort are difficult to evaluate. Some patients may have had UTI recurrences diagnosed and treated in another center. In addition, several patients were prescribed antimicrobial prophylaxis, which further complicates the analysis of patterns of UTI recurrence. However, 15 of the 28 patients (54%) who both underwent a VCUG and had a UTI recurrence also had high-grade VUR. Very few patients underwent follow-up imaging to identify renal scars or functional renal impairment, which may be of far greater significance than VUR status. In conclusion, the AAP guidelines seem justifiable for imaging studies in children aged 2–24 months with febrile UTI. The most important argument supporting this conclusion is that very few patients with actionable findings would have been missed had the guidelines been applied, while a significant number of unnecessary VCUGs would have been avoided. Based on this retrospective study, however, the guidelines cannot be conclusively recommended, as a larger, prospective study is needed to determine the true effectiveness of the guidelines. Acknowledgement Dr Robert Paul provided assistance with language and grammar. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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