Evaluation of the Pediatric Patient Who Has Had a Febrile UTI: What Do We Know, and What Should We Do? Paul Brakeman, MD, PhD Assistant Professor, Medical Director, Pediatric Dialysis Unit November 11, 2010

Why obtain radiologic imaging after a febrile UTI? Identify and treat anatomical abnormalities such as vesico-ureteral reflux (VUR), posterior urethral valves and duplicated collecting systems. VUR is by far the most common anatomical abnormality discovered on imaging Prevent: recurrence of UTIs damage to kidneys (as measured by scarring on DMSA scan) hypertension chronic kidney disease Because the most recent (1999) written guidelines from the AAP recommended obtaining radiologic imaging

AAP Practice Guidelines Practice Parameter: The Diagnosis Treatment, and Evaluation of the Initial Urinary Tract Infection in Febrile Infants and Young Children. April 1, 1999 “After a 7- to 14-day course of antimicrobial therapy and sterilization of the urine, infants and young children 2 months to 2 years of age with UTI should receive antimicrobials in therapeutic or prophylactic dosages until the imaging studies (sic renal ultrasound and VCUG) are completed (strength of evidence: good).” http://aappolicy.aappublications.org/cgi/reprint/pediatrics;103/4/843.pdf

Important to note which patients are not included in these guidelines Older pediatric patients – these patients should be carefully evaluated for signs and symptoms of voiding dysfunction and constipation before any radiologic evaluation is undertaken Patients with afebrile cystitis are also excluded from this guideline; although, in the 2 months to 2 year cohort, most are unable to verbalize the difference between cystitis and pyelonephritis and are almost always identified by having fever.

So the conundrum in pediatrics is that UTI is a common problem (~1 So the conundrum in pediatrics is that UTI is a common problem (~1.5% of ALL girls will have a UTI by age 2) and VUR is commonly found in patients who have had a UTI (~30% will have a positive VCUG) but renal failure is an uncommon problem so evaluating every infant who has had a febrile UTI for urinary tract anomalies means that many VCUG’s and ultrasounds will need to be performed to prevent the rare cases of end-stage renal failure……

In addition, there is little prospective, controlled evidence that any of the current treatments that are implemented for VUR prevent renal damage, hypertension, or the onset of end-stage renal disease. In that context, why do I care about VUR?

Reflux nephropathy is a major cause of end-stage renal disease in pediatrics NAPRTCS 2006 Annual Report

Recurrent UTIs have significant morbidity Discomfort and pain for the patient Lost work and cost for the parents Occasional hospitalization for co-morbid symptoms

Development of the Uretero-vesicular Junction (UVJ) Viana, et al., Development 2007

Grading of VUR on VCUG Grade I: Ureteral involvement w/o dilation Grade II: Ureteral and collecting system involvement w/o dilation Grade III. Mild ureteral and collecting system dilation w/ mild calyceal blunting Grade IV: Grossly dilated ureter and collecting system w/ moderate calyceal blunting. Grade V: Massively dilated and tortuous ureter and collecting system. Papillary impression no longer visible in most calyces.

An example of VUR Grade 2 Grade 1 www.cocuknefroloji.com/vur5.jpg

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

Most low-grade VUR (Grades I-III) resolves over time, and even some high-grade VUR resolves Zerati-Filho, Int Brazil J Urol, 2007

Scarring is present at birth in some patients with VUR – indicating that some scarring seen in patient with VUR is not necessarily related to postnatal events but rather to prenatal development RD = renal damage, NI = not imaged Infants diagnosed with prenatal hydro were evaluated with VCUG and DMSA at 2 months of life Silva, Peds Neph 2006

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

When do you need to test for VUR? That is still too hard to answer – let’s look some more at what other data is available

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

What is the treatment for VUR? Do nothing, i.e. close clinical observation – not evaluated by any prospective trials until recently Use antibiotic prophylaxis to reduce episodes of pyelonephritis and clinical observation to identify and treat new episodes of pyelo Surgically correct reflux by ureteral reimplantation Endovesical anti-reflux procedure using Dextranomer Hyaluronic Acid injection at the ureteral orifice to remodel the orifice and create a non-refluxing valve

What treatment works? Actually, let’s rephrase that, what treatment works to cure the VUR? Do nothing – most low grade reflux resolves spontaneously, so that works to “cure” low grade reflux Antibiotic prophylaxis - most low grade reflux resolves spontaneously, so that works to “cure” low grade reflux also Surgically correction corrects VUR ~ 99% of the time Endovesical anti-reflux procedure is also highly successful for grades 1-3 and less so for grades 4-5

What treatment works best to prevent renal damage?

What treatment works best to prevent renal damage? That is unclear

What treatment works best to prevent renal damage? Two older studies demonstrated that for grades III + IV, early surgical treatment and daily antibiotic prophylaxis were equivalent in their ability to prevent new renal scars: 19/155 medically-treated and 20/151 surgically treated developed new renal scarring by intravenous urography (Smellie Peds Neph 1992 and Birmingham Reflux Study Group BMJ 1994) Actually, unclear whether either treatment prevented the development of new renal scars, because there was no control group of patients who received only clinical observation There was a lower rate of febrile UTI in the surgically treated cohorts. These trials did not include a placebo or control arm with no treatment and close clinical observation and prompt treatment

What treatment works best to prevent renal damage? There is some evidence that early diagnosis of UTI is important in preventing scarring. Smellie and colleagues reported that the highest risk of scarring was in patients for whom diagnosis of UTI was delayed for at least 5 days with acute urinary tract symptoms or fever OR for a month with ill-defined symptoms such as abdominal pain So close clinical observation is important for patients managed conservatively

What new data do we have about treatments for VUR What new data do we have about treatments for VUR? Specifically we have new data antibiotic prophylaxis Randomized controlled trials Garin et al., Pediatrics, 2006 Roussey-Kesler et al. J Urol 2008 Pennesi et al. Pediatrics 2008 Montini et al. Pediatrics 2008 Craig et al. NEJM 2009 One very large retrospective cohort study Conway et al. JAMA, 2007

Randomized controlled trials Garin et al., Pediatrics, 2006*** Roussey-Kesler et al. J Urol 2008*** Pennesi et al. Pediatrics 2008*** Montini et al. Pediatrics 2008*** Craig et al. NEJM 2009 One very large retrospective cohort study Conway et al. JAMA, 2007*** *** Showed no benefit of antibiotic prophylaxis to prevent febrile UTIs or new scarring

What can be gleaned from these negative trials? The rate of recurrent UTI varied from 12% for a population of patients with and without VUR (Conway et al.) to ~33% for a population of patients with Grades II-IV VUR (Pennessi et al.) The rate of recurrence of UTI appears to increase for increasing Grade of VUR Sub-group analysis of boys with Grade 3 VUR by Roussey-Kesler et al. showed some benefit of prophylaxis but with <20 subjects in each arm indicating that perhaps in some groups with higher grade reflux prophylaxis might have benefit All the trials were too small to demonstrate a modest benefit Rate of new scarring was small (< 5%) and there was no benefit of prophylaxis in preventing scars

Randomized controlled trials Garin et al., Pediatrics, 2006 Roussey-Kesler et al. J Urol 2008 Pennesi et al. Pediatrics 2008 Montini et al. Pediatrics 2008 Craig et al. NEJM 2009*** One very large retrospective cohort study Conway et al. JAMA, 2007 *** Showed a modest benefit of decreasing the number of recurrent UTIs from 19% to 13%

What was different about Craig et al.? Larger clinical trial adequately powered to detect a modest difference (288 pts in each arm) In order to get the larger patient population, they enrolled all patients <18 years of age with “symptomatic” UTI. Not febrile UTIs, just symptomatic UTIs. >80% of males were uncircumcised 23% had VUR Grades III to V There did appear to be the most benefit in patients with VUR III-V Risk of new scarring was small (~5%) and there was no benefit of prophylaxis in preventing new scarring

Meta-analysis of the prophylaxis trials Mathew et al. Indian Pediatrics 2010

Meta-analysis of the prophylaxis trials Mathew et al. Indian Pediatrics 2010

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

What is the best radiologic test to obtain following a UTI What is the best radiologic test to obtain following a UTI? - Hoberman, et al. 2003

What is the best radiologic test to obtain following a UTI What is the best radiologic test to obtain following a UTI? - Hoberman, et al. 2003 309 children (276 girls and 33 boys) aged 1-24 months Inclusion criteria: First febrile UTI Temperature of at least 38.3°C (rectal) at presentation or within 24 hours positive urine culture with at least 50,000 colony-forming units per milliliter, representing a single pathogen) Patients recruited from ED population Secondary evaluation of previously published paper comparing IV antibiotics to oral antibiotics for the treatment of UTI

Hoberman, et al. 2003 Ultrasound and DMSA were obtained within 72 hours Patient were placed on daily antibiotic prophylaxis VCUG was obtained at one month Follow-up DMSA was obtained at 6 months

VCUG results - Hoberman, et al. 2003 39% were found to have VUR 96% was low grade – I-III

Ultrasound results - Hoberman, et al. 2003

Ultrasound is not a good test to detect VUR - Hoberman, et al. 2003

Ultrasound is not a good test to detect VUR – but can detect high grade VUR

Conclusions - Hoberman, et al. 2003 Ultrasound is not good at detecting VUR and only rarely detects significant other abnormalities VCUG primarily detects Grade I-III reflux – which resolves most of the time Renal scarring was present in 9.2% of patients and new scarring did not appear in the 6 months post-UTI

What is the best radiologic test to obtain following a UTI What is the best radiologic test to obtain following a UTI? - Hoberman, et al. 2003 “An ultrasound performed at the time of acute illness is of limited value. A voiding cystourethrogram for the identification of reflux is useful only if antimicrobial prophylaxis is effective in reducing re-infections and renal scarring.”

Important clinical questions in the diagnosis and management of VUR What is the natural history of VUR? When do you need to test for VUR? What is the treatment for VUR?

Most VCUG’s identify low-grade VUR (Grade I-III) AND If medical management with daily antibiotic prophylaxis is equivalent to surgical management of low-grade VUR and daily antibiotic prophylaxis is not better than nothing or, at most, not much better than nothing, then is there any current efficacious treatment for low-grade VUR aside from clinical observation and early diagnosis and treatment of recurrent pyelonephritis? AND If clinical observation and early diagnosis and treatment of pyelonephritis is adequate (perhaps even the best) treatment for VUR, then does one need to attempt to diagnose VUR in pediatric patients who present with a first time febrile UTI?

Who are the patients at higher risk for having significant pathology such as posterior urethral valves, severe reflux and anatomical abnormalities and for having the worst outcome from recurrent UTI? Males of all ages who have had a febrile UTI are at higher risk for anatomical abnormalities Infants less than 2 months would seem to be at higher risk for UTI related consequences Older children at the age of potty training are more likely to develop UTI related to abnormal bladder function secondary to voiding dysfunction due to voiding behavior or constipation and thus are at lower risk of anatomical abnormalities Patients with afebrile UTI’s – especially in school age children are at lower risk for anatomical abnormalities Patients who have had more than one febrile UTI are probably at higher risk for having significant pathology, although this has not been proven

When and what do you need to do to evaluate patients radiologically following a UTI? First, complete a thorough history and exam Other unrecognized UTI’s in the past? Loss of or delayed motor milestones indicating abnormal neurologic function? Signs of constipation or voiding dysfunction? Family history of reflux, anatomical abnormalities, renal hypoplasia/dysplasia? Was there a 3rd trimester fetal ultrasound obtained? Normal blood pressure? Normal urologic anatomy on exam? Normal spine anatomy on exam? Normal, symmetric strength and tone in the lower extremities?

When and what do you need to do to evaluate patients radiologically following a UTI? Radiologic evaluation should be less frequent than our current practice pattern. For females > 2 months and who are not potty-training, VCUG and ultrasound evaluation should be postponed until a second febrile UTI has occurred. Given a theoretical increased risk of complications of recurrent UTI, younger infants < 2 months probably merit a more thorough evaluation including ultrasound and VCUG. In addition with limited data available and a possible small benefit of prophylactic antibiotics, it is reasonable to start these patients on prophylactic antibiotics until an evaluation has been obtained. Ultrasound and VCUG should be strongly considered in any male with a febrile UTI – especially if circumcised or uncircumcised > 1 year old

When and what do you need to do to evaluate patients radiologically following a UTI? For female and male patients older than 2 years and who are potty-training, a careful history should be obtained to evaluate for voiding dysfunction and constipation as these are likely causes of UTI in this age group, and for females ultrasound and VCUG should not be performed in this age group unless indicated based on abnormal findings on history or physical. For afebrile UTI’s without obvious signs of pyelo, ultrasound and VCUG should not be obtained. It seems reasonable but not cost effective to obtain an ultrasound after febrile UTIs for any of the patients described above as it appears not to cause harm. However, it may lead to unnecessary additional evaluation of incidental findings with no clinical significance I only use prophylactic antibiotics in patients for whom I am going to obtain imaging (i.e. young infants and males) and if high grade reflux or other anatomical abnormality is discovered