AAP Clinical Guideline: The Diagnosis and Management of the Initial Urinary Tract Infection in Febrile Infants and Young Children (2011) from the Executive Committee Section on Urology American Academy of Pediatrics AAP UTI Guidelines • Aim to enhance the clinical diagnosis of UTI in children 2 months to 2 years • Rationalize the use of antibiotics for pediatric UTI • No VCUG for first time febrile UTI with normal US No VCUG for first time febrile UTI with normal US? • Treatment of Vesicoureteral Reflux with prophylactic antibiotics has not been “proven” to prevent febrile UTI • Treatment of VUR has not be “proven” to prevent renal injury • Therefore, why make the diagnosis? Why are we concerned about the recommendation NOT to perform a VCUG after the first febrile UTI? • Data and interpretation are flawed • Guidelines are not “real-world” • Inadequate safety net Reflux: The Good, the Bad, and the Ugly • Reflux is a heterogeneous, complex condition that can be benign, cause significant renal injury with lifelong implications, or fall somewhere in between • The ability to distinguish between these groups is critical to determining level of risk and treatment • Our ability to make those distinctions is limited Data and interpretation are flawed Historical perspective • 11 to 27 year follow-up of 72 children hospitalized for UTI 18% dead 8% progressive renal failure 22% persistent untreated or recurrent UTI Steele et al., NEJM 1963 3 UTIs per patient year 2.5 2 Pre CAP (24) 1.5 On CAP (19) 1 0.5 0 CAP Only CAP and Surgery Evidence Based Medicine • How good is the evidence?  wide age ranges,  few patients with higher than grade II VUR,  variable culture methods,  low incidence of initial renal abnormalities,  no assessment of medication compliance,  no assessment of voiding dysfunction • “…the studies were insufficiently powered for an analysis according to the grade of reflux.” Montini et al. , NEJM, 2011 Study biases • Many of the studies started with a diagnosis of VUR • Parents and physicians were not blinded to the presence of VUR • Their behavior reflects knowledge of VUR – they will likely act differently than if they did not know VUR was present Roussey-Kessler, et al. J Urol. 179:674, 2008 UTI-free Craig, et al., Antibiotic prophylaxis and recurrent urinary tract infection in children. NEJM 361:1748-59, 2009. Febrile UTI Swedish Reflux Trial: J. Urol. 184:286, 2010 Swedish Reflux Study: New Renal Scarring at 2 years Number of patients with new renal damage in 2 years FU Combining Studies • Combining data from multiple flawed studies introduces multiple statistical risks • Amalgamation paradox (Simpson’s Paradox) Result of combining studies of differing sizes Often due to a “lurking” variable that is not accounted for ? Bladder/bowel dysfunction UTI incidence with CAP: Impact of BBD BBD BBD Overall 3650 Non-BBD No BBD *†‡ * 2020 5850 *† 5850 21040 21040 700 6040 *†‡ 6040 0 20 40 60 80 UTI incidence (per 100 children) 100 0 20 40 60 80 UTI incidence (per 100 children) 43% incidence if BBD present vs. 12% if no BBD 100 The Promise and Problems of MetaAnalysis • Meta-analysis may still be improved, by a combination of experience and theory, to the point at which its findings can be taken as sufficiently reliable when there is no other analysis or confirmation available, but that day seems to be well ahead of us. LeLorier et al. also imply, however, that large randomized, controlled trials should be regarded more circumspectly than published reports commonly suggest. We never know as much as we think we know. John C. Bailar, III, M.D., Ph.D. N Engl J Med. 1997 Aug 21;337(8):559-61. Guidelines are not “real world” General Pediatrician's assessment of a UTI • Common referral: “UTI – please evaluate” • Uncommonly acknowledgement of febrile vs. afebrile • Rarely a formal urinalysis • May only have dipstick of urine • Often no culture obtained • Never an assessment of voiding behavior • 70% adherence to recommended method of urine collection • 61% adherence to recommended imaging work-up Perceptual problems • Reflux is being “decriminalized” and being seen as a homogeneously “benign” condition • This is the same narrow perceptual view as that where all reflux was seen as dangerous • UTI is a warning sign for risk; ignoring it once may send the wrong message to family and practitioner • A diagnosis of VUR improves the ability of the family and pediatrician to respond appropriately Inadequate safety net Safety nets: Effectiveness depends on their porosity Why evaluate a child after a febrile UTI? • Identify risk of recurrence • Identify risk of renal injury • Identify treatable contributors • Can we eliminate all risk? NO • Can we reduce risk? YES • What is an acceptable threshold for risk and how much are we willing to “pay” for this in testing morbidity, cost, false positives, etc.? Risk thresholds • “We over-treat in order to avoid under-treatment” • What level of risk is acceptable and how do we measure the impact over time? • Who should determine the level of acceptable risk? Patients/parents? Government? Physicians? Insurance companies? What is the risk of missing reflux? Overall scarring incidence is “low” Is it low enough? Coulthard (Ped Nephrol 2009) – scarring can be severe Grade of reflux correlates with scarring More episodes of infection correlate with increased incidence of scarring • Delays in therapy can be associated with more renal injury • • • • • • New scars in refluxing children usually with delayed treatment, absence of antibiotic prophylaxis, and social problems 75 (%) Number of UTIs and percent with DMSA abnormalities 100 50 Boys 25 Girls 0 0 1 >2 7 6 Relative Risk VUR grade and risk of DMSA abnormalities 5 4 3 2 1 0 I II II IV-V Swerkersson, et al., J Urol 178:647, 2007 Risk of Renal Scarring depending on presence or absence of VUR Shaikh et al., Pediatrics 126, 2010 AAP UTI Evaluation Guidelines • Presume to establish a safety threshold that has never been debated in the professional community and which is essentially a societal choice and not a medical one • Has based conclusions on limited and flawed data that have a very narrow scope of applicability • Makes recommendations that are highly unlikely to be accurately or effectively followed by most “real-world” pediatricians who are swamped with paperwork and routine clinical problems AAP UTI Evaluation Guidelines AAP OBLIGATIONS • Vigorously support education of pediatricians in the  recognition,  clinical evaluation, and  stratification of UTI, including voiding dysfunction • Follow-up assessment of adherence to Guidelines • Assessment of clinical impact of Guidelines in terms of population incidences of acute pyelonephritis and renal damage Six Papers: Prophylaxis versus No Prophylaxis 1) 2) 3) 4) 5) 6) Pennesi et al, Pediatrics 2008 Garin et al, Pediatrics 2006 Montini et al Pediatrics 2008 Roussey-Kesler et al, J Urol 2008 Craig et al, NEJM 2009 Brandström et al, J Urol 2010 Problem 1 • Sex and Circumcision Status – – – – – – Pennesi: 50% male, all uncircumcised* Garin: 17% male, unknown Montini: 31% male, unknown* Roussey-Kesler: 31% male, unknown* Craig: 36% male, 4% circumcised* Brandström: 37% male, unknown* * Circumcision not widely practiced – skews culture results Problem 2 • Bagged Urine Specimens used in the studies: – – – – – Pennesi Montini Roussey-Kesler Craig Brandström • Catheterized Urine Specimens: – Garin • A major concern especially in uncircumcised males Problem 3 • Age – Brandström: 1-2 year olds – Craig: median age 14 months, 37% older than 2 years, 23% were between 4 and 15 years – Garin: 1 mo to 18 years, median in abx and no-abx group was 2 years old, PN patient age unknown – Montini: median 10.2 months (1-8.4 years) – Pennesi: mean 9 months, (2-84 months) – Roussey-Kesler: median 1 yr, ± SD: 8.4 mos • Older patients: bladder/bowel dysfunction (BBD) issues Problem 4 • USN can’t determine scarring – Moorthy I, et al, Pediatr Nephrol 19:153, 2004 – Tasker AD et al, Clin Radiol 47: 177, 1993 • USN can’t determine VCUG – Blane CE, et al, J Urol 150:752, 1993. • DMSA scans not uniformly performed: – Pennesi – Roussey-Kesler – Craig • VCUG and USN not performed on all patients – Craig • Incomplete imaging - ? Who really has what ? Who really had scarring? Problem 5 • Compliance of antibiotic regimen NOT assessed – – – – – Pennesi (yes in those with recurrent UTI, 100%!?) Garin Roussey-Kesler Craig Brandström • Montini: Yes, 71% compliance • No Prophylaxis versus Non-Compliance isn’t the same as Prophylaxis versus No Prophylaxis Problem 6 • Blinded or placebo controlled: – Craig • None of the other studies were blinded or conducted with placebo – Pennesi – Montini – Roussey-Kesler – Garin – Brandström Problem 7 Pennesi: no benefit to prophylaxis Garin: no benefit Montini: prophylaxis may benefit grade III Roussey-Kesler: prophylaxis may benefit boys with grade III • Craig: febrile UTI double in those not on prophylaxis • Brandström: prophylaxis provides clear benefit, no new scarring on prophylaxis • Contradictory conclusions – yet Guidelines declares otherwise… • • • • Yule Simpson Effect !? • Combining data can yield contradictory results – Karl Pearson, Udny Yule, Edward Simpson New Drug Old Drug Cancer + 150 (15%) 190(19%) Remission 850 (85%) 810 (81%) p = 0.020 Men Men Women Women New Drug Old Drug New Drug Old Drug Cancer + 80 (16%) 100 (20%) 70 (14%) 90 (18%) Remission 420 (84%) 400 (80%) 430 (86%) 410 (82%) p= 0.12 p= 0.10