The RIVUR [Randomized Intervention for Children With Vesicoureteral Reflux] trial investigators set out to reevaluate the role of antimicrobial prophylaxis for the prevention of recurrences in children with vesicoureteral reflux. As recent randomized trials have produced conflicting results, the goal of the RIVUR investigators was to determine whether antimicrobial prophylaxis could prevent febrile or symptomatic urinary tract infection and whether prevention would reduce the likelihood of subsequent renal scarring. The results, recently published in the New England Journal of Medicine (2014;370:2367-76), demonstrated that nearly 18% of children, 2 months to 6 years of age, have a febrile or symptomatic recurrence within the first year after the initial or presenting episode. The recurrence rate for febrile or symptomatic episodes was reduced by approximately 50% in the treatment group (trimethoprim-sulfamethoxazole) to nearly 8%.
In addition, the proportion of children considered treatment failures (defined as a combination of febrile or symptomatic UTIs or development of new renal scarring) occurred twice as often in the placebo group as in the treatment group. However, despite the reduction in febrile or symptomatic episodes in the treatment group, approximately 8% of children in both treatment and placebo groups developed new renal scarring, as defined by a decreased uptake of tracer or cortical thinning.
Dr. Stephen I Pelton
The study confirmed that children with higher grades of reflux (III or IV at baseline) were more likely to have febrile or symptomatic recurrences, that children with bladder and bowel dysfunction (based on a modified Dysfunctional Voiding Symptom Score) also were more likely to have febrile or symptomatic recurrences, and that recurrences in children on prophylaxis were more likely to be resistant to trimethoprim-sulfamethoxazole than were those in children on placebo.
Implications for prevention of UTI
The American Academy of Pediatrics guidelines for the management of UTI in children were updated in 2011 (Pediatrics 2011;128:595-610). The authors contacted the six researchers who had conducted the most recent randomized controlled trials and completed a formal meta-analysis that did not detect a statistically significant benefit of prophylaxis for stopping the recurrence of febrile UTI/pyelonephritis in infants without reflux or those with grades I, II, III, or IV. The 2011 recommendations reflected the findings of an AAP subcommittee that antimicrobial prophylaxis was not effective, as had been presumed in a 1999 report (Pediatrics 1999;103:843-52).
The AAP subcommittee on urinary tract infection of the Steering Committee on Quality Improvement and Management – authors of the 2011 revised guidelines – have recently reviewed the RIVUR study data (AAP News, July 1 2014) and concluded that antimicrobial prophylaxis did not alter the development of new renal scarring/damage, that the benefits of daily antimicrobial prophylaxis were modest, and that the increased likelihood of resistance to trimethoprim-sulfamethoxazole at recurrences was significant. The subcommittee reaffirmed the 2011 guidance concerning a "less aggressive" approach: Renal and bladder ultrasound are adequate for assessment of risk for renal scarring at first episodes, and watchful waiting without performing voiding cystourethrography (VCUG) or initiating prophylaxis is appropriate. VCUG is indicated after a first episode if renal and bladder ultrasonography reveals hydronephrosis, scarring, or other findings that would suggest either high-grade vesicoureteral reflux (VUR) or obstructive uropathy and in other atypical or complex clinical circumstances. As well, VCUG also should be performed if there is a recurrence of a febrile UTI (Pediatrics 2011;128:595-610).
The current subcommittee opined that prompt diagnosis and effective treatment of a febrile UTI recurrence may be of greater importance, regardless of whether VUR is present or the child is receiving antimicrobial prophylaxis.
My take
For me, the RIVUR data provide further insights into both the risk of any recurrence (approximately 18% by 12 months, approximately 25% by 24 months) and the risk for multiple recurrences (approximately 10%). The data identify those at highest risk for recurrences (patients with bladder and bowel dysfunction or higher grades of reflux) and provide evidence that trimethoprim-sulfamethoxazole prophylaxis is highly effective in such groups. No serious side effects were observed during the RIVUR trial; however, Stevens-Johnson syndrome is documented to occur rarely after administration of trimethoprim-sulfamethoxazole, and the potential for this life-threatening event should be part of the decision process. I believe the value of the new data is that they provide confidence that antimicrobial prophylaxis can be effective for the prevention of febrile/symptomatic UTI, and that in select children at great risk for recurrences and subsequent renal damage, antimicrobial prophylaxis can be part of our toolbox.
Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said that he had no relevant financial disclosures.