The overall problem of managing UTI in children between 2

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1 AMERICAN ACADEMY OF PEDIATRICS Stephen M. Downs, MD, MS Technical Report: Urinary Tract Infections in Febrile Infants and Young Children ABSTRACT. Overview. The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement has analyzed alternative strategies for the diagnosis and management of urinary tract infection (UTI) in children. The target population is limited to children between 2 months and 2 years of age who are examined because of fever without an obvious cause. Diagnosis and management of UTI in this group are especially challenging for these three reasons: 1) the manifestation of UTI tends to be nonspecific, and cases may be missed easily; 2) clean voided midstream urine specimens rarely can be obtained, leaving only urine collection methods that are invasive (transurethral catheterization or bladder tap) or result in nonspecific test results (bag urine); and 3) a substantial number of infants with UTI also may have structural or functional abnormalities of the urinary tract that put them at risk for ongoing renal damage, hypertension, and endstage renal disease (ESRD). Methods. To examine alternative management strategies for UTI in infants, a conceptual model of the steps in diagnosis and management of UTI was developed. The model was expanded into a decision tree. Probabilities for branch points in the decision tree were obtained by review of the literature on childhood UTI. Data were extracted on standardized forms. Cost data were obtained by literature review and from hospital billing data. The data were collated into evidence tables. Analysis of the decision tree was used to produce risk tables and incremental cost-effectiveness ratios for alternative strategies. Results. Based on the results of this analysis and, when necessary, consensus opinion, the Committee developed recommendations for the management of UTI in this population. This document provides the evidence the Subcommittee used in the development of its recommendations. Conclusions. The Subcommittee agreed that the objective of the practice parameter would be to minimize the risk of chronic renal damage within reasonable economic constraints. Steps involved in achieving these objectives are: 1) identifying UTI; 2) short-term treatment of UTI; and 3) evaluation for urinary tract abnormalities. Pediatrics 1999;103(4). URL: cgi/content/full/103/4/e54; urinary tract infection, infant, child; decision analysis; cost-effectiveness analysis; vesicoureteral reflux. ABBREVIATIONS. UTI, urinary tract infection; VUR, vesicoureteral reflux; IVP, intravenous pyelography; VCUG, voiding cystourethrography; RCG, radionuclide cystourethrography; ESRD, end-stage renal disease; IUTI, initial UTI; CFU, colonyforming unit; UA, urinanalysis; OR, odds ratio; LE, leukocyte esterase; UNC, University of North Carolina; WBC, white blood cells; HPF, high-power field; SMX, sulfamethoxazole; TMP, trimethoprim. The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. PEDIATRICS (ISSN ). Copyright 1999 by the American Academy of Pediatrics. METHODS Analysis of the data on UTI consisted of several steps. The Subcommittee met to define the target population, setting, and providers for whom the practice parameter is intended. Subcommittee members identified the outcomes of interest for the analysis. A conceptual evidence model of the diagnosis and management of UTI was developed. The evidence model was used to generate a decision tree. A comprehensive review of the literature determined the probability estimates used in the tree. The tree was used to conduct risk analyses and cost-effectiveness analyses of alternative strategies for the diagnosis and management of UTI. Based on the results of these analyses and consensus when necessary, an algorithm representing the strategies with acceptable risk benefit trade-offs was developed. EVIDENCE MODEL The overall problem of managing UTI in children between 2 months and 2 years of age was conceptualized as an evidence model (Fig 1). The model depicts the relationships between the steps in the diagnosis and management of UTI. The steps are divided into the following four phases: 1) recognizing the child at risk for UTI, 2) making the diagnosis of UTI, 3) short-term treatment of UTI, and 4) evaluation of the child with UTI for possible urinary tract abnormality. Phase 1 represents the recognition of the child at risk for UTI. Age and other clinical features define a prevalence or a priori probability of UTI, determining whether the diagnosis should be pursued. If children at sufficiently high risk for UTI are not identified for diagnostic evaluation, the potential benefit of treatment will be lost. However, children with a sufficiently low likelihood of UTI should be saved the cost of diagnosis (and perhaps misdiagnosis) of UTI when the potential for benefit is minimal. Phase 2 depicts the diagnosis of UTI. Alternative diagnostic strategies may be characterized by their cost, sensitivity, and specificity. The result of testing is the division of patients into groups according to a relatively higher or lower probability of having a UTI. The probability of UTI in each of these groups depends not only on the sensitivity and specificity of the test, but also on the prior probability of the UTI among the children being tested. In this way, the usefulness of a diagnostic test depends on the prior probability of UTI established in phase 1. Overdiagnosis of UTI may result in unnecessary treatment and unnecessary imaging evaluation for urinary tract abnormalities. Underdiagnosis will result in missing the opportunity to treat the acute infection and the consequences of possible underlying urinary tract abnormalities. Phase 3 represents the short-term treatment of UTI. Alternatives for treatment of UTI may be compared, based on their likelihood of clearing the initial UTI (IUTI). Phase 4 depicts the imaging evaluation of infants with the diagnosis of UTI to identify those with urinary tract abnormalities such as vesicoureteral reflux (VUR). Children with VUR are believed to be at risk for ongoing renal damage with subsequent infections, resulting in hypertension and renal failure. 1 3 Prophylactic antibiotic therapy or surgical procedures such as ureteral reimplantation may prevent progressive renal damage. Therefore, identifying urinary abnormalities may offer the benefit of preventing hypertension and renal failure. Each alternative strategy for imaging evaluation can be characterized according to its cost, invasiveness, and test characteristics (sensitivity and specificity). The potential yield of an imaging evaluation will be affected by the accuracy of the initial diagnosis of UTI. If the probability of UTI is low because a nonspecific test was used to make the Downloaded from by PEDIATRICS guest on August Vol. 16, No. 4 April of60

2 Fig 1. Evidence model for UTI guideline. The evidence model traces steps in the evaluation and management of childhood UTI from clinical suspicion to urinary tract imaging. diagnosis, the cost of an imaging study will yield little benefit. Therefore, the value of imaging strategies depends on the accuracy of the diagnosis of UTI in phase 2. Because the consequences of detection and early management of UTI are affected by subsequent evaluation and long-term management and, likewise, long-term management of patients with UTI depends on how they are detected at the outset, the Subcommittee elected to analyze the entire process from detection of UTI to the evaluation for, and consequences of, urinary tract abnormalities. Decision Tree The conceptual model was used to develop a decision tree (Fig 2). The tree quantifies the relationship between alternative strategies for the diagnosis and treatment of UTI, the evaluation of children for abnormalities of the urinary tract, and the anticipated consequences of these alternative diagnostic and treatment strategies. The tree is read from left to right. The square branch points (decision nodes) represent alternatives under the control of the caregiver. The round chance nodes represent the chance events that may be affected by the alternatives chosen. A computerized version of the decision tree was constructed and used for the analyses presented. In the diagnosis and treatment of UTI, four alternatives are represented. As anchor points, the alternatives of treating all or treating none of the patients at risk are represented. Two alternative tests are represented in the other branches. The test characteristics and costs of these tests were adjusted to correspond with the tests the Subcommittee chose to evaluate. In this way, the Subcommittee compared alternative testing strategies. In the decision tree, if a testing strategy is used, the result is positive or negative. A positive result was assumed to lead to a decision to treat and a negative result to a decision to observe without treatment. If treatment is chosen, presumptively or based on the results of a diagnostic test, a treatment complication may result. Rarely, as in the case of anaphylaxis, the complication may result in death. For all other patients, there is a risk of urosepsis. 4 This risk is the probability of UTI multiplied by the prevalence of urosepsis among infants with UTI. Assuming urosepsis behaves like bacteremia from other sources in infants, 5 the infection may clear spontaneously in those who have urosepsis. The probability of clearing the infection is increased among those who receive antimicrobials. If urosepsis does not clear, hospitalization will result, and the child has a risk of dying. Once the short-term outcome of the UTI has been resolved, the second decision is whether and how to image the urinary tract for structural and functional abnormalities. The three following options are modeled: 1) a full evaluation, including ultrasonography or an intravenous pyelogram and voiding cystourethrography (VCUG) or radionuclide cystourethrography (RCG); 2) ultrasonography alone; and 3) no evaluation. The results of the evaluation are determined separately for each patient type. For patients who have no UTI (false-positive diagnosis of UTI), it is assumed that abnormalities are not present and the infant is not at increased risk of renal damage. Patients who have a true UTI may or may not have VUR. Among those with VUR, the reflux may be low grade (1 or 2) or high grade (3, 4, or 5). The probability of having a positive result when imaging an abnormal urinary tract depends on the sensitivity of the imaging modality for the abnormality. For example, ultrasonography is much more sensitive to high-grade VUR than to low-grade VUR. 6 The analysis assumes that all imaging modalities have 100% specificity (ie, no false-positive diagnoses). The result of the imaging evaluation would be used to select a treatment (surgical correction or antibiotic prophylaxis as appropriate) to prevent recurrent infections. An evaluation with normal results or no evaluation would lead to no therapy. Identifying the optimal therapy for a given urinary tract abnormality is beyond the scope of the present analysis. Patients may or may not have recurrent UTI, defined as more than three infections in a 5-year period. Recurrent infections lead to progressive renal scarring. The risk of scarring is highest among those with high-grade VUR and lowest among those with no VUR. 7 Therapeutic interventions reduce the risk of renal scarring by reducing VUR in the case of surgery or preventing infection in the case of antimicrobial prophylaxis. Patients with progressive renal scarring are at increased risk of hypertension and ESRD. Those who do not experience these outcomes may have decreased renal function but will not have clinically important outcomes. At the terminal nodes of each branch, the outcomes are tabulated as costs and clinical outcomes. Costs considered include the cost of diagnostic testing, treatment, complications of treatment, hospitalization for urosepsis, imaging studies, surgery or prophylaxis, management of hypertension, and ESRD. Clinical outcomes include chronic hypertension, renal failure, and death. The decision tree was encoded and evaluated using the Decision Maker software Version 6.0 (Sonnenberg and Pauker, New England Medical Center, Boston, MA). Literature Review Articles for review were obtained from four sources in two rounds of searching. In the first round, the MEDLINE database was searched using four separate search strategies corresponding with the four phases of the diagnosis and treatment of UTI: recognition, diagnosis, short-term treatment, and imaging evaluation (Appendix 1). The titles and abstracts resulting from these searches were distributed among the Subcommittee members who identified those that were definitely or potentially useful. These articles were reproduced in full. In a second round of searching, articles were identified from three additional sources: the bibliographies of two recent reviews 8,9 ; a survey of the members of the Subcommittee, soliciting the articles they identified as most important and relevant to the analysis; and articles sought specifically to estimate costs for the management of chronic hypertension and ESRD. At each of the two rounds of searching, the articles were reviewed by the epidemiology consultant, and articles with no original data were removed. The remaining articles were reviewed and data extracted using a data extraction form designed to identify estimates necessary to evaluate the decision model (Appendix 2). In addition, the quality of each article was rated on a scale from 0 to 1 by using quality criteria adapted from Sackett and colleagues. 10 Reviewers also provided a subjective rating of good, fair, or poor to each article. Data extracted were recorded in evidence tables, using an 2of60 AMERICAN ACADEMY Downloaded OFfrom PEDIATRICS by guest on August 16, 2018

3 Fig 2. The UTI decision tree models the decision-making processes in the diagnosis and management of UTI. This model was used for cost-effective analyses. Downloaded from by guest on August 16, of60

4 Excel (Microsoft Corporation, Redmond, WA) spreadsheet. A subset of 24 articles was reviewed twice by different reviewers to check interrater reliability. At the time of analysis of the decision models, the articles were reviewed again by the epidemiology consultant. RESULTS Literature Review The results of the literature searches are shown in Fig 3. In the initial MEDLINE search, 1949 articles were identified. The title and abstract of each of these was reviewed by two members of the Subcommittee and identified as useful, potentially useful, or not useful. After this review and elimination of duplicates, 430 articles were reproduced in full for data extraction. Of these, 105 were rejected because they contained no original data relevant to the analysis. In the second round, an additional 133 articles were identified. Twenty-six of these were rejected for lack of original data. A total of 432 articles were reviewed at least once. The quality of the articles in this area is highly variable (Fig 4), but most articles met 50% or fewer of the quality criteria. Interrater reliability for quality scores was tested using a subset of the articles (Fig 5). Correlation of scores among reviewers was only fair (r 0.43). Correlation among the readers subjective ratings was less good (r 0.29). Fig 3. The literature review process. The diagram illustrates the number of articles examined and reviewed or rejected from the analysis. Evidence Tables Probability of UTI The prevalence of UTI among febrile infants between 2 and 24 months of age is 5% (Table 1). The references in Table 1 are ordered by decreasing relevance and decreasing quality scores. The references are divided additionally into two categories. The studies of infants having fever without an obvious cause are presented in the top of the table, and studies of symptomatic infants who do not strictly meet the criterion of fever without an obvious cause are presented in the bottom. The pooled prevalence represents the prevalence that is derived by pooling the data from the first 11 articles in the table. The studies are very consistent, and the pooled prevalence is insensitive to the addition or deletion of any one of them. The first three articles are cross-sectional prevalence studies of UTI in febrile infants younger than 12 months 11 or children younger than 24 months. 12,13 The data in the fourth reference 14 are a subset of the study population that was younger than 6 months. North 15 concluded that there was not a significant prevalence of UTI among febrile children. However, the prevalence derived from the small subset of patients younger than 2 years who had colonyforming units (CFUs) is consistent with the findings from other studies. The studies by Baker and Arner, 16 Kramer and associates, 17 and Buys and colleagues 18 have some potential for work-up selection bias because the decision to obtain a urine specimen for culture was made by the care provider. Therefore, these studies may slightly underestimate the prevalence of UTI because specimens were not obtained and cultured from all eligible patients. However, these biases would be small. The study by Pylkkanen and associates 19 is the only outlier. The prevalence figure is based on a small subset of symptomatic infants who were reported as having fever only. This study is of lower quality than the others but cannot be excluded on any other basis. However, its small sample has little effect on the pooled prevalence. Included in Table 1 are results from three other studies that do not examine febrile infants per se. The first 20 reports a prevalence for 187 children younger than 5 years with febrile seizures. Interestingly, the prevalence is quite similar to that of children with fever alone. Siegel and colleagues 21 studied children with a variety of symptoms, including fever. The prevalence again is close to 5%. The study by Pryles and Luders 22 gives the prevalence of UTI among infants with diarrhea. In an effort to identify subgroups of febrile infants at sufficiently low risk of UTI that they could be excluded from additional evaluation, the Subcommittee studied clinical risk factors that reduce the probability of UTI (Table 2). Factors identified were patient age, gender, circumcision, and the presence of other identifiable sources of fever. Age and Gender The data indicate that the probability of finding UTI in febrile male infants is less than half that in 4of60 AMERICAN ACADEMY Downloaded OFfrom PEDIATRICS by guest on August 16, 2018

5 Fig 4. Quality histogram plots the distribution of quality scores among the articles reviewed. Quality scores were assigned by reviewers based on predetermined criteria. Fig 5. Quality score agreement. A sample of articles was reviewed twice by different reviewers. The graph plots the scores assigned by one reviewer versus the score assigned by the other reviewer. The correlation coefficient r represents only fair agreement. females, and just greater than one third for males between 1 and 2 years of age (Table 2). Findings from two studies, by Roberts and associates 13 and by Hoberman and colleagues, 23 report the prevalence of UTI by gender in an unbiased sample of febrile infants younger than 1 year. The studies show inconsistent results among males younger than 1 year. Roberts and co-workers 13 found no males with UTI, whereas Hoberman and associates 23 found a prevalence of 2.5%. Among females, the prevalence was similar, 7.4% and 8.8%, respectively. Other studies also suggest a lower risk among males in older age groups. 24,25 Other studies used to estimate the effect of age and gender on the prevalence of UTI examined only children with confirmed UTI. Relative risk of UTI for a given gender was estimated from these studies using the odds ratio (OR), P(male UTI)/P(female UTI). Because this prevalence in males and females in the general population is 50%, the OR is essentially the Downloaded from by guest on August 16, of60

6 TABLE 1. Prevalence of UTI Author Year Sample Size Prevalence 95% CI Comments Quality Score Hoberman et al Febrile infants in an emergency room Good 1 setting Roberts et al Febrile infants in an emergency room Good 1 setting Bonadio Chart review of febrile infants with no Fair 1 source of fever who are admitted to rule our sepsis Bauchner et al Infants 3 to 37 months, temperature Good C North Infants 2 years, temperature 38 C, Fair 0.66 in emergency and outpatient clinics Baker and Arner Febrile children in an emergency Fair 0.66 department Kramer et al Retrospective study of febrile infants 3 Good 0.66 to 24 Months in an emergency room Ginsburg and to 8-Month-old boys Good 1 McCracken 4 Buys et al Birth to 3 years with fever, selected, Fair 0.66 UTI suspected Pylkkanen et al Substratum of study population; Fair 0.63 children 1 year with fever only Pooled Prevalence Total Pooled Prevalence Studies of different, but related populations McIntyre et al Children 2 years who had febrile Good 1 convulsions Siegel et al Infants with a various symptoms, FTT, Good 1 fever, rash, dysuria, diarrhea, irritability Pryles and Luders Hospitalized patients Poor 0 same as the ratio of the prevalence of UTI among males to the prevalence among females. The prevalence itself can be derived by assuming an overall prevalence of 5% for both genders and a 50% prevalence of males in the population, using the formula, P(UTI male) P(male UTI) P(UTI)/P(male). The comparable formula was used for females. Studies also were stratified by age (Table 2). These data and the data for prevalence by gender were used to make crude estimates of the effect of age and gender on the prevalence of UTI in four subgroups: males younger than 1 year (3%), males older than 1 year (2%), females younger than 1 year (7%), and females older than 1 year (8%). Circumcision Data from Wiswell and co-workers, Ginsberg and McCracken, 4 and Craig 29 show a dramatic risk reduction among circumcised males. Most (but not all) of these data are retrospective, and the studies are plagued with missing data, but the findings are quite consistent. In all these studies, the probability of circumcision given UTI [P(circ UTI)] was reported. Relative risk was estimated by the OR, P(circ UTI)/ P(no circ UTI). Estimates of prevalence of UTI given circumcision [P(UTI circ)] were calculated by assuming the previous probability of UTI regardless of circumcision status [P(UTI)] is 5%, and the probability of circumcision (among males) is 70%. 27 Prevalences are calculated using these estimates and Bayes formula, P(UTI circ) P(circ UTI) P(UTI)/ P(circ). The results suggest that the prevalence of UTI among febrile male infants who are circumcised would be 0.2%. Most data come from studies of infants younger than 1 year, but the effect seems to persist even beyond infancy, 30 and Craig 29 did not find that age younger or older than 1 year confounded the effect of circumcision. The bottom of Table 2 shows how the relative risk affects the probability of UTI assuming a prevalence of 5%. Making the (reasonable) assumption that circumcision status is independent of age, circumcised males older than 1 year are at lowest risk. Interestingly, circumcision could account for the gender differences in prevalence. If one assumes that febrile females and uncircumcised males have a UTI prevalence of 7%, that circumcised males have a prevalence of 0.2%, and that 70% of males are circumcised, then the prevalence of UTI among males would be ( ) ( ) or 2%, a figure consistent with the data. Tests for UTI When an infant is considered to be at significant risk for UTI, the next step is to make the diagnosis. Choosing diagnostic criteria for UTI involves two competing considerations. A false-negative diagnosis will leave patients with UTI at risk for serious complications. A false-positive diagnosis may lead to unnecessary, invasive, and expensive testing. In evaluating alternative diagnostic tests for UTI, the Subcommittee defined as a gold standard any bacterial growth on a culture of urine obtained by suprapubic bladder aspiration (tap), ie, any bacterial growth on a culture of a urine specimen obtained by tap defines a UTI. For the analysis, a culture of a urine specimen 6of60 AMERICAN ACADEMY Downloaded OFfrom PEDIATRICS by guest on August 16, 2018

7 TABLE 2. Risk Factor Risk Factors for UTI Relative Risk Prevalence, % Sample Size* Author Date Source Gender Male ( 1 y) Roberts et al (13) Male ( 1 y) Hoberman et al (12) Male (3 8 mo) Ginsburg and McCracken (4) Male (0 1 y) Jodal (66) Male (1 2 y) Jodal (66) Male (0 10 y) Jodal (66) Male (1 12 mo) Elzouki et al (93) Male (1 5 y) Elzouki et al (93) Weighted average, Male ( 1 y) Weighted average, Male ( 1 y) Female ( 1 y) Roberts et al (13) Female ( 1 y) Hoberman et al (12) Female (3 8 mo) Ginsburg and McCracken (4) Female (0 1 y) Jodal (66) Female (1 2 y) Jodal (66) Female (0 10 y) Jodal (66) Female (1 12 mo) Elzouki et al (93) Female (1 5 y) Elzouki et al (93) Weighted average, Female ( 1 y) Weighted average, Female ( 1 y) Circumcision Wiswell et al (26) Wiswell and Roscelli (27) Wiswell and Hachey 1993 no # (28) Ginsburg and McCracken (4) Weighted average * Different studies report different outcomes. Thus, the data cannot be pooled. The sample size refers to the number of subjects in the entire study. The weighted average is weighted by this number. These studies examined only children with UTI. In these studies, relative risk is estimated by OR as P (male UTI)/P(female UTI). The prevalence is derived by assuming an overall prevalence of 5% for both genders and a 50% prevalence of males in the population, using the formula, P(UTI male) P(male UTI) P(UTI)/P(male). A comparable formula is used for females. Only the probability of circumcision given UTI [P(circ UTI)] is reported. Relative risk is estimated by OR, P(circ UTI)/P(no circ UTI). Estimates of prevalence of UTI given circumcision [P(UTI circ)] are calculated by assuming the previous probability of UTI regardless of circumcision status [P(UTI)] is 5%, and the probability of circumcision (among males) is 70%. Prevalences are calculated using these estimates and Bayes s formula: P(UTI circ) P(circ UTI) P(UTI)/P(circ). obtained by a tap was considered to have 100% sensitivity and specificity. However, this was not always used for comparisons in studies of other diagnostic strategies. Alternative diagnostic strategies fall into the three following areas: 1) urine analysis (UA) for immediate diagnostic information, 2) culture of a urine specimen obtained by urine bag or transurethral catheterization, and 3) culture of a urine specimen using the dipslide culture technique. The sensitivities and specificities of the diagnostic tests reviewed are shown in two formats. Table 3 lists the test characteristics. In part A, data are listed by study; in B, they are listed by type of test. C presents a summary of the test characteristics of each of the tests. Figure 6 plots the sensitivities and specificities of the tests on a graph with axes corresponding to a receiver operating characteristic curve. The true-positive rate (sensitivity) is on the vertical axis, and the false-positive rate (1, specificity) is on the horizontal axis. Tests that plot nearest to the top left corner of the graph have the greatest diagnostic value. The diagonal represents test characteristics with no diagnostic value, and tests that plot below the diagonal may be misleading. The tests are identified by type (leukocyte esterase [LE], nitrite, blood, protein, microscopy for bacteria or white blood cells, combinations of tests, or special tests). UA The various components of the UA include the reagent slide tests, ie, LE, nitrite, blood, and protein, and microscopic examination for leukocytes or bacteria. The diagnostic characteristics of these tests have been evaluated individually and in combination (Table 3). Tests can be combined serially, meaning all test results must be positive for the combination to be positive or, in parallel, meaning a positive result on any one of the tests defines a positive result for the combination. The serial strategy maximizes specificity at the expense of sensitivity, whereas parallel testing maximizes sensitivity at the expense of specificity. Perhaps the most commonly used component of the UA used to evaluate a child who may have a UTI is the reagent strip (dipstick). Tests for UTI that are available on most reagent strips include the LE, nitrite, blood, and protein. The test characteristics of each of these are given in Table 3. The LE is the most sensitive single test. Its reported sensitivity ranges from 67% in a screening setting 31 in which symptoms and, therefore, inflammation, would not be expected, to 94% in settings in which UTI is suspected. 32 The specificity of LE generally is not as good. However, because the specificity describes the performance of Downloaded from by guest on August 16, of60

8 8of60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018 TABLE 3, A. Characteristics of Diagnostic Tests for UTI Listed by Study, in Descending Order of Quality Score Author Title Date Score Quality Comments Test Sensitivity, % Conatantinos Kunin and DeGroot 94 Nitrite indicator strip test for bacteriuria Sensitivity of a nitrite indicator strip method in detecting bacteriuria in preschool girls Specificity, % Good Gold standard was culture by urine dipslide Nitrite Fair Gold standard was culture by urine dipslide Nitrite Hoberman et al 12 Prevalence of urinary tract Good Heavy bacteria infection in febrile infants 10 WBC/HPF WBC/HPF Any WBC/HPF Any bacteria Lowe 95 Chemical screening and Fair Gold standard was culture on CLED agar Nitrite prediction of bacteriuria a Protein new approach Blood strip Nitrite or protein Nitrite or blood Nitrite blood protein Corman et al 96 Simplified urinary microscopy to Good WBC ( 10/HPF) detect significant bacteriuria WBC ( 5/HPF) Bacteriuria ( 5/HPF) Bacteriuria ( 10/HPF) Vickers et al 97 Diagnosis of urinary tract infection in children: fresh urine microscopy or culture? Fair Bias, no clear gold standard, sensitivity calculated by the reviewer using culture as gold standard and uncertain microscopy results as negative; gold standard: culture of bag urine 10 million CFU Microscopy Lohr et al 36 Making a presumptive diagnosis Fair to Prevalence biased; examines the test Dipstick, leukocyte of urinary tract infection by good characteristics of various parallel and Nitrite using a urinalysis performed in serial combinations of components of the Microscopy, leukocytes an on-site laboratory urine analysis Leukocytes or nitrite LE and nitrite or leukocytes Leukocytes or bacteria Bacteria LE, nitrite, or leukocytes Any test positive Bixler-Forell Clinical evaluation of three rapid Good to Pediatric and adult patients; study of urine Lumac et al 42 methods for the detection of fair cultures; no patient data; inpatients and Bac-T-screen significant bacteriuria outpatients; no exclusion of antibiotic users; tables incomplete; gold standard culture with CFU AMS

9 Downloaded from by guest on August 16, of60 TABLE 3, A. Continued Author Title Date Score Quality Comments Test Sensitivity, % Leong and Tan 44 Bladder aspiration for diagnosis of urinary tract infection in infants and young children Fair Gold standard was culture of urine obtained by suprapubic aspiration Specificity, % Urine bag Hoberman et al 33 Pyuria and bacteriuria in urine Good Studies on urine microscopy 10 WBC/mm specimens obtained by catheter WBC/mm 3 and any bacteria from young children with fever Any bacteria on microscopy Littlewood et al 35 Comparison between Good 10 Bacteria/HPF, centrifuged microscopical examination of unstained deposits of urine and quantitative culture deposit examination 10 Bacteria/HPF, uncentrifugated deposit examination Pryles et al 98 A comparative study of bacterial Good Any count cultures and colony counts in paired specimens of urine obtained by catheter versus voiding from normal infants and infants with urinary tract infection Goldsmith and Comparison of urine dipstick, Fair Diagnostic test for bacteriuria and not LE Campos 99 microscopy, and culture for the UTI (urine specimen), gold standard Nitrite detection of bacteriuria in children 10 5, clean catch urine Microscopy Marsik et al 100 Use of the leukocyte esterase and nitrite tests to determine the need for culturing urine specimens from a pediatric and adolescent population Good Although reviewer tends to consider articles good, may be confusing with useful information; gold standard, culture excluding contamination Tahirovic and A modified nitrite test as a Good to Gold standard, clean catch Initial nitrite Pasic 41 screening test for significant fair CFU Modified nitrite bacteriuria Hoberman et al 40 Enhanced urinalysis as a Good Study compares enhanced to standard Enhanced urinalysis screening test for urinary tract urinalysis; gold standard is culture Urinalysis infection Enhanced urinalysis Weinberg and Urine screen for bacteriuria in Good Gold standard is culture with Gram stain, any organism Gan 34 symptomatic pediatric CFU Dipstick, nitrite outpatients WBC, 10/HPF WBC, 5/HPF LE LE or nitrite Gram stain 1/OIF LE Nitrite

10 10 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018 TABLE 3, A. Continued Author Title Date Score Quality Comments Test Sensitivity, % Aronson et al 101 Shannon et al 48 Aronson et al 101 Shannon et al 48 Pfaller et al 31 Barbin et al 50 Combined suprapubic aspiration and clean-voided urine examination in infants and children The diagnosis of bacteriuria by bladder puncture in infancy and childhood Combined suprapubic aspiration and clean-voided urine examination in infants and children The diagnosis of bacteriuria by bladder puncture in infancy and childhood The usefulness of screening tests for pyruia in combination with culture in the diagnosis of urinary tract infection Simplified microscopy for rapid detection of significant bacteriuria in random urine Good Gold standard was culture of urine by suprapubic aspiration Specificity, % Clean-voided urine Fair Clean-catch urine Good Gold standard was culture of urine by suprapubic aspiration Clean-voided urine Fair Clean-catch urine Good Chamber count of WBCs LE Good to fair specimens Lam et al 38 Pyuria and bacteriuria Fair Gold standard was culture with CFU Simplified microscopy of urine specimen WBC 10/1.6 mm Boreland and Dipstick analysis for screening of Good to Visually read nitrite Stoker 102 paediatric urine fair Visually read blood Visually read protein Photometrically read protein Photometrically read blood Photometrically read nitrite Visually read nitrite, blood, or protein Photometrically read nitrite, blood, or protein Cannon et al 103 Rapid screening and Good Ames nitrite microbiologic processing of Bio-Dynamics nitrite pediatric urine specimens Bio-Dynamics 15-minute LE test Bio-Dynamics 1-minute LE test Bio-Dynamics nitrite with minute LE test Bio-Dynamics nitrite with 15- minute LE test

11 Downloaded from by guest on August 16, of 60 TABLE 3, A. Continued Author Title Date Score Quality Comments Test Sensitivity, % Pylkkanen et al 19 Diagnostic value of symptoms Fair Gold standard was culture by Leukocytes 200/mL and clean-voided urine suprapubic aspiration Bacterial count, numerous specimen in childhood urinary Urine bag changed hourly until urine Culture of bag urine tract infection obtained Houston 39 Pus cell and bacterial counts in Fair The gold standard is the clinical Pyuria 50/cmm the diagnosis of urinary tract diagnosis of urinary tract infection Culture with CFU infections in childhood One or the other Goossens et al 104 Prevalence of asymptomatic Fair to Gold standard was standard culture on Nitrite bacteriuria and comparison good CLED medium Dipslide between different screening methods for its detection in children Wiggelinkhuizen Dipstick screening for urinary Fair A study comparing different brands of LE Multistix et al 32 tract infection urine dipstick tests for urine analysis Nitrite m Nitrite c Leukocytes and nitrite m Leukocytes and nitrite c LE Combur Leukocytes or nitrite m Leukocytes or nitrite c Hoberman et al 105 Cost-effective screening for urinary tract infection (UTI) in young children with fever 1994 NA Good Abstract only Pyuria 10 WBC/mm Specificity, %

12 TABLE 3, B. Characteristics of Diagnostic Tests for UTI Listed by Test Author Quality Score Subjective Quality Test Sensitivity, % Specificity, % Leukocyte esterase Goldsmith and Campos Fair LE Marsik et al Good LE Pfaller et al Good LE Lohr et al Good Dipstick, LE Wiggelinkhuizen et al Fair LE Multistix LE Combur Weinberg and Gan Good LE Cannon et al Good Bio-Dynamics 15-minute LE test Bio-Dynamics 1-minute LE test Nitrite Goldsmith and Campos Fair Nitrite Marsik et al Good Nitrite Tahirovic and Pasic Good to fair Nitrite Kunin and DeGroot Fair Nitrite Lowe Fair Nitrite Sinaniotis et al Good Nitrite Boreland and Stoker Good to fair Visually read nitrite Photometrically read nitrite Lohr et al Good Nitrite Goossens et al Fair/good Nitrite Wiggelinkhuizen et al Fair Nitrite m Nitrite c Weinberg and Gan Good Dipstick, nitrite Cannon et al Good Ames nitrite Bio-Dynamics nitrite Microscopy, bacteria Pylkkanen et al Fair Bacterial count, numerous Lohr et al Good Bacteria Hoberman et al Good Any bacteria Heavy bacteria Hoberman et al Good Any bacteria Weinberg and Gan Good Gram stain, any organism Gram stain, 1/OIF Houston Fair /mm Littlewood et al Good 10 Bacteria/HPF, centrifugated deposit examination 10 Bacteria/HPF, uncentrifugated deposit examination Corman et al Good Bacteriuria, 5/HPF Bacteriuria, 10/HPF Microscopy, leukocytes Pfaller et al 0.45 Good Chamber 58.0 count Pylkkanen et al Fair Leukocyte, 200/mL Lohr et al Good Microscopy, leukocyte Hoberman et al Good Any WBC/HPF WBC/HPF WBC/HPF Hoberman et al Good 10 WBC/mm Weinberg and Gan Good WBC, 10/HPF WBC, 5/HPF Houston Fair Pyuria, 50/mm Lam et al 38 WBC, 10/1.6 mm Corman et al Good WBC, 10/HPF WBC, 5/HPF Microscopy, leukocytes Hoberman et al Good 5 WBC Hoberman et al 105 Good Pyuria, 10 WBC/mm Protein Lowe Fair Protein Boreland and Stoker Good to fair Visually read protein Photometrically read protein of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

13 TABLE 3, B. Blood Author Continued Quality Score Subjective Quality Test Sensitivity, % Specificity, % Lowe Fair Blood strip Boreland and Stoker Good to fair Visually read blood Photometrically read blood Combinations Lowe Fair Nitrite and protein Nitrite or blood Nitrite or blood and protein Nitrite or blood or protein Boreland and Stoker Good to fair Visually read nitrite or blood and protein Photometrically read nitrite or blood and protein Lohr et al Good Leukocytes and nitrite LE and nitrite or leukocytes Leukocytes or bacteria LE, nitrite, and/or leukocytes Any positive test Wiggelinkhuizen et al Fair Leukocyte esterase and nitrite m Leukocyte esterase and nitrite c Leukocyte esterase or nitrite m Leukocyte esterase or nitrite c Hoberman et al Good Urinalysis (standard) Enhanced urinalysis Weinberg and Gan Good LE or nitrite Cannon et al Good Bio-Dynamics nitrite with minute LE test Bio-Dynamics nitrite with minute LE test Goldsmith and Campos Fair Microscopy Vickers et al Poor Microscopy Barbin et al Good to fair Simplified microscopy of urine Hoberman et al Good WBC/mm 3 and any bacteria Houston Fair 50 WBC/HPF or CFU by culture (gold standard is clinical diagnosis) Special Tahirovic and Pasic Good to fair Modified nitrite (urine incubated with nitrate) Bixler-Forell et al Good to fair Lumac Bac-T screen AMS the test on specimens from patients without a UTI, it is highly dependent on patient characteristics. The reported specificity varies from 63% to 92%. The test for nitrite has a much higher specificity (90% to 100%) and lower sensitivity (16% to 82%). For this reason, nitrite may be useful for ruling in UTI when it is positive, but it has little value in ruling out UTI. Dipstick tests for blood and protein have poor sensitivity and specificity with respect to UTI. Therefore, the use of results for blood or protein from dipstick testing has a high likelihood of being misleading. Carefully performed microscopic examination of the urine has high sensitivity and specificity in many studies (Table 3; Fig 6). However, the wide range of reported test characteristics of microscopy for leukocytes or bacteria (Table 3, C) presumably reflects the difficulty of performing these tests well and the hazards of performing them poorly. In studies that have shown the best test characteristics, tests were performed by on-site laboratory technicians who often used counting chambers. When examining the urine for bacteria, unstained 33 and Gram-stained 34 specimens seem to be effective. However, centrifugation of the specimen reduces the specificity of the test. 35 The number of bacteria also is important. Using heavy bacterial counts as a diagnostic criterion results in low sensitivity and high specificity. 12 The reverse applies when observation of any bacteria is considered a positive test. 34 Microscopy for leukocytes is variably sensitive (32% to 100%) and specific (45% to 97%). Studies with accurate results generally used mirrored counting chambers, on-site technicians, or both. 33,36 Specimens also must be examined shortly after collection. A 3-hour delay results in a 35% drop in sensitivity. 37 Finally, if the number of leukocytes considered abnormal is high, the test will be insensitive, 19 if the number is low, it will be highly sensitive. 38 The reverse is true for specificity. Downloaded from by guest on August 16, of 60

14 TABLE 3, C. Test Characteristics of Diagnostic Tests for UTI Summarizing Diagnostic Characteristics of Each Test Sensitivity Range Sensitivity Median Sensitivity Mean Specificity Range Specificity Median Specificity Mean Leukocyte esterase Nitrite Blood Protein Microscopy, leukocytes Microscopy, bacteria LE or nitrite Any positive test on urine analysis Fig 6. Reported sensitivity and specificity of diagnostic tests for UTI plotted on receiver operating characteristic curve coordinates. Also shown is the threshold line for a two-way sensitivity analysis on sensitivity and specificity. The plot shows a wide variation in reported test characteristics. Only those above and to the left of the threshold line would have sufficient sensitivity and specificity to supplant urine culture as a gold standard diagnostic test. Test characteristics resulting from combinations of UA components are shown separately (Table 3, B; Fig 6). Parallel combinations of tests maximize sensitivity. This is supported by the data presented in Table 3. Studies using careful technique in on-site laboratories found that a parallel combination of microscopy for leukocytes and bacteria had a sensitivity of 99% or greater, 33,36,39,40 and UA, considering any component positive as a positive UA result, has 100% sensitivity and 60% specificity. 36,39 A number of special tests have been evaluated for the diagnosis of UTI. The first is a modified nitrite test. 41 This involves incubating a urine specimen for several hours with added nitrite before testing for nitrate. The reported sensitivity and specificity are 93% and 88%, respectively. However, comparable results have not been reported. Immunochemical studies for early detection of bacterial growth 42 have not had impressive results. Obtaining a Urine Specimen The Subcommittee defined the gold standard definition of a UTI to be growth on a culture of a urine specimen obtained by tap. Often, however, performance of a bladder tap is resisted because it is invasive. Moreover, bladder taps may not yield urine specimens. Success rates for obtaining urine specimens vary between 23% and 90% Although 100% success has been achieved when using ultrasonographic guidance, 18 practitioners often use 14 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

15 Downloaded from by guest on August 16, of 60 TABLE 4. Drug Effectiveness of Short-term Therapies for UTI Grouped by Duration and Agent Duration, d Sample Size Clinical Notes Efficacy, % 95% CI for Efficacy Weighted Average, % Pooled 95% CI Comments Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y, at 4 d Amoxicillin 1 dose 108 after treatment Amoxicillin 4 24 CRP Amoxicillin 4 d 55 Amoxicillin CRP Amoxicillin CRP Amoxicillin y Amoxicillin y Amoxicillin y Amoxicillin mo 14 y Amoxicillin 10 8 Cx-at 17 d, 2 18 y Amoxicillin y Amoxicillin y Amoxicillin y, at 4 d after treatment Amoxicillin y Amoxicillin 10 d 112 Ampicillin mo 12 y Ampicillin Average 5 y Ampicillin mo 11 y Augmentin y Cefodroxil 1 Dose mo Cefodroxil mo Keflex y Keflex mo 12 y Nitrofurantoin mo 12 y Pipemidic acid y Pipemidic acid y Pivmecillinam y SMX mo 14 y SMX mo 12 y Sulfametrizole y Sulfametrizole y TMP 1 Dose y TMP-SMX 1 Dose mo 11 y TMP-SMX 1 Dose 42 3 mo 12 y TMP-SMX 1 Dose 39 3 mo 12 y TMP-SMX 1 dose 58 TMP-SMX mo 12 y TMP-SMX 1 61 TMP-SMX mo 12 y TMP-SMX mo 12 y TMP-SMX 3 23 Cx-, 3 mo 16 y TMP-SMX 3 d 121 TMP-SMX mo 12 y TMP-SMX mo 12 y TMP-SMX y TMP-SMX mo 12 y TMP-SMX mo 11 y TMP-SMX 7 d 120 TMP-SMX mo 10 y TMP-SMX mo 12 y References

16 16 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018 TABLE 4. Drug Continued Duration, d Sample Size Clinical Notes Efficacy, % 95% CI for Efficacy Weighted Average, % Pooled 95% CI Comments TMP-SMX Cx-at 17 d, 2 18 y TMP-SMX Cx-, 3 mo 16 y TMP-SMX y TMP-SMX mo 5 y TMP-SMX y TMP-SMX mo 12 y TMP-SMX 10 d 113 Various mo 15 y Various mo 15 y Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y Amoxicillin 1 Dose y, at 4 d after Amoxicillin 1 dose 108 treatment Cefodroxil 1 Dose 36 2 mo 16 m TMP-SMX 1 Dose mo 11 y TMP 1 Dose y TMP-SMX 1 Dose 42 3 mo 12 y TMP-SMX 1 Dose 39 3 mo 12 y TMP-SMX mo 12 y TMP-SMX 1 dose 61 Pivmecillinam y Sulfametrizole y TMP-SMX mo 12 y TMP-SMX mo 12 y TMP-SMX 3 23 Cx-, 3 mo 16 y TMP-SMX 3 d 121 Various mo 15 y Amoxicillin 4 24 CRP Amoxicillin 4 d 55 Pipemidic acid y Augmentin y TMP-SMX mo 12 y TMP-SMX mo 12 y TMP-SMX y TMP-SMX mo 12 y TMP-SMX mo 11 y TMP-SMX 7 d 120 Amoxicillin CRP Amoxicillin CRP Amoxicillin y Amoxicillin y Amoxicillin y Amoxicillin mo 14 y Amoxicillin 10 8 Cx- at 17 d, 2 18 y Amoxicillin y Amoxicillin y Amoxicillin y, at 4 d after treatment Amoxicillin y Amoxicillin 10 d 112 Ampicillin mo 12 y Ampicillin Average 5 y Ampicillin mo 11 y Cefodroxil mo 16 m References

17 TABLE 4. Continued Comments References Pooled 95% CI Weighted Average, % 95% CI for Efficacy Clinical Notes Efficacy, % Sample Size Drug Duration, d Keflex y Keflex mo 12 y Nitrofurantoin mo 12 y Pipemidic acid y SMX mo 14 y SMX mo 12 y Sulfametrizole y TMP-SMX mo 10 y TMP-SMX mo 12 y TMP-SMX Cx- at 17 d, 2 18 y TMP-SMX Cx-, 3 mo 16 y TMP-SMX y TMP-SMX mo 5 y TMP-SMX y TMP-SMX mo 12 y TMP-SMX 10 d 113 Various mo 15 y transurethral catheterization or urine bags to obtain urine specimens for culture. Cultures of urine specimens obtained by catheterization have a specificity of 83% to 89% compared with cultures of urine specimens obtained by tap. 8,11,45 However, if only cultures yielding 1000 CFU/mL are considered positive, catheterization cultures have a 95% sensitivity with a specificity of 99%. Cultures of bag urine specimens are 100% sensitive, but they have a specificity between 14% and 84%. 44,46 48 Therefore, because UTI is present in a small minority (5%) of patients tested, use of culture results from urine specimens obtained from the bag to rule in UTI is likely to result in large numbers of false-positive results. Specifically, with a prevalence of 5% and specificity of 70%, the positive predictive value of a positive culture of bag urine specimens would be 15%. That is, 85% of positive cultures of urine specimens obtained from a bag would be falsepositive results. Culturing Techniques The standard culturing technique involves streaking on blood agar and MacConkey media. More recently, dipslide methods have been developed. The few studies of dipslide cultures that were reviewed reported sensitivities between 87% and 100% and specificities between 92% and 98%. 47,49,50 Consequences of a Missed Diagnosis of UTI If the diagnosis of UTI is not made because it was not suspected or a test of insufficient sensitivity was used, three consequences may result. The first (see Prevalence of Urinary Tract Abnormalities ) is the lost opportunity to find a urinary tract abnormality that could result in renal damage. The second is the formation of new renal scars. Although repeated UTI lead to scarring (see Progressive Renal Damage ) and progressive scarring is associated with hypertension and ESRD, the role of scarring from a single UTI in long-term clinical consequences is unknown. Nevertheless, timely treatment of febrile UTI in children appears to be important in preventing scars. 51 The third consequence of missing the diagnosis of UTI results from the urosepsis that occurs in a small proportion of febrile infants with UTI. 4,52 Among patients with febrile UTI, in the age group to which this analysis applies, the risk of concurrent bacteremia is between 2.2% 52 and 9%. 4 The natural history of bacteremia in infants with febrile UTI is not described. Common pediatric experience is that septic shock and death are rarely seen in this situation, suggesting that spontaneous resolution of bacteremia occurs in this situation as it does in others. 53,54 However, evidence exists that among infants with bacteremia attributable to Escherichia coli in the presence of a UTI, fatality rates may be as high as 10% to 12%. 5 Short-term Treatment of UTI In studying the short-term treatment of UTI, the two following issues were addressed: 1) What do the data suggest about the duration of outpatient antibiotic therapy? and 2) What is the best choice for Downloaded from by guest on August 16, of 60

18 18 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018 TABLE 5. Majd et al 125 Farnsworth et al 126 Prevalence of VUR Among Children With UTI Author Title Design Score Grade Prevalence of VUR, % Relationship among vesicoureteral reflux, p-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection The detection of reflux nephropathy in infants by 99m Technetium dimercaptosuccinic acid studies Sample Size Average Age Minimum Age Maximum Age Female, % Comments Cohort 0.27 Poor 31.0 Children with febrile UTI Clinical trial Good y 47.0 Cohen et al 127 Postcircumcision urinary tract infections Cohort retrospective Poor y 66.8 Children 1 y admitted with UTI Lomberg and Svanborg 128 Influence of P blood group phenotype on susceptibility to urinary tract infection Cohort 0.12 Fair Referral-selected population, recurrent pyelonephritis Snodgrass 129 Relationship of voiding dysfunction to urinary tract infection and vesicoureteral reflux in children wk 3 y Referral urologic clinic for UTI de Man 130 Bacterial attachment, inflammation and renal First UTI scarring in urinary tract infection Chiu et al 131 Urinary tract infections in children Case series Poor y 36.2 Hospital admission with proven UTI by Cx Ginsburg and McCracken 4 Urinary tract infections in young infants Case-series Good mo 5 d 8 mo 38.0 Hospital with acute UTI Dickinson 132 Elzouki et al 93 Jodal 66 Incidence and outcome of symptomatic urinary tract infection in children Symptomatic urinary tract infection in pediatric patients: a developmental aspect The natural history of bacteriuria in childhood Burbige et al 133 Urinary tract infection in boys Case series, Cohort 0.5 Good Symptomatic UTI; Reflux estimated by hydronephrosis (may underestimate) Cross-sectional Poor mo 13 y 66.3 Symptomatic UTI, inpatient and outpatient Cohort 0.5 Good y 81.0 Cases of Sx UTI among all children, ie, population-based incidence Poor wk 14 y 0.0 First UTI Cohort Welch et al 134 Recurrent urinary tract infection in girls 0.12 Poor y 2 y 9 y Recurrent UTI ( 5) Selkonet et al 135 Covert bacteriuria in schoolgirls in Newcastle Cohort 0.72 Good y 18 y Asymptomatic upon Tyne: a 5-year follow-up Hashemi 119 Recurrent urinary tract infection Cohort: 0 Poor mo 12 y 74.0 Symptomatic UTI diagnostic test Verrier-Jones et al 136 Glomerular filtration rate in schoolgirls with covert bacteriuria Cohort 0.91 Good y 11 y Covert bacteriuria; may be biased estimate of reflux, not all screened McKerrow et al 3 Urinary tract infection in children Cohort 0.62 Fair y 60.0 Previous confirmed UTI Verber and Meller 7 Chao et al 85 Thelle and Siskjaer 137 Development of renal scars after acute nephronia in childhood: a study of sequential DMSA scans Vesicoureteric reflux and renal scarring in children: a local perspective Combined 99mTc DMSA kidney scintigraphy and [131]Hippuran renography in children with urinary tract infections Cohort 0.5 Fair y 12 d 4 y? Symptomatic UTI; prevalence based on kidneys Cohort Fair mo Cohort: diagnostic test? Fair male, 3 y; female, 7 y 5 mo 14 y 84.0 Referral patients for imaging evaluation

19 Downloaded from by guest on August 16, of 60 TABLE 5. Continued Author Title Design Score Grade Prevalence of VUR, % Sample Size Average Age Minimum Age Maximum Age Tappin et al 138 A prospective study of children with first Cohort 0.75 Good y 74.0 acute symptomatic E coli urinary tract infection Lanning et al 139 Prediction of vesicoureteral reflux children from intravenous urography films 19.0 Cremin 140 Observations on vesicoureteric reflux and intrarenal reflux: a review and survey material Cohort 0.5 Fair wk 12 y 54.0 Whyte et al 141 A protocol Cohort 0.75 Poor y 7 y? Ben-Ami et al 142 Imaging of children with urinary tract infection: a tailored approach Case report Fair y 81.0 First UTI Drachman et al 143 Excretory urography and cystourethrography Case series Fair mo 12 y 93.0 First UTI in the evaluation of children with urinary tract infection Drew and Acton 144 Radiological findings in newborn infants Case series d 16.0 with urinary infection Moncrieff and Value of cystography in urinary tract Case series Fair y 10 d 9.5 y recurrent UTI Whitelaw 145 infections Bourchier et al 146 Radiological abnormalities in infants with Case series Fair to mo 5 d 1 y 32.0 First UTI Verber et al 147 Ring and Zobel 148 Verber and Meller 149 Ozen and Whitaker 150 Cohen 49 Monahan and Resnick 151 Mok and White 152 Jequier et al 153 Middleton and Nixon 154 Redman and Seibert 155 urinary tract infections 99mTc dimercaptosuccinic acid (DMSA) scan as first investigation of urinary tract infection Urinary infection and malformations of urinary tract in infancy Serial 99mTc dimercaptosuccinic acid (DMSA) scans after urinary infections presenting before the age of 5 years Does severity of presentation in children with vesicoureteric reflux relate to the severity of the disease or the need for operation? The first urinary tract infection in male children Urinary tract infections in girls: age at onset and urinary tract abnormalities The value of radiological investigation in paediatric urinary tract infection The value of ultrasonography as a screening procedure in a first-documented urinary tract infection in children The lack of correlation between upper tract changes on excretory urography and significant vesicoureteral reflux The role of excretory urography in the evaluation of girls with urinary tract infection Female, % poor Case series Good y 0 59 y 70.0 First UTI Cohort Fair Median, 4 d 12 mo 45.0 First UTI 3mo Cohort 0.75 Fair d 4.9 y 67.0 First UTI Cohort 0.5 Good y 3 mo 16 y 61.3 First UTI Comments Cohort 0.62 Good mo 14 y 0.0 First UTI; all boys Case series Good mo 36 mo Recurrent UTI y 15 y Cross-sectional 0.18 Fair y 80.8 Symptomatic UTI Cohort 0.18 Fair d 15 y 50.4 First UTI; examination at acute phase Case-series y Retrospective, children with UTI examined with IVP VCUG y 14 y? Referral group, history of UTI, urology department

20 20 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018 TABLE 5. Continued Author Title Design Score Grade Prevalence of VUR, % Baker and Barbaris 156 Kenda et al 157 Smellie et al 158 Johnson et al 159 Traisman et al 160 Marshall et al 161 Blickman et al 162 Comparative results of urological evaluation of children with initial and recurrent urinary tract infection Renal ultrasound and excretory urography in infants and young children with urinary tract infection Children with urinary infection: a comparison of those with and without vesicoureteric reflux Identification of children requiring radiologic evaluation for urinary infection The localization of urinary tract infection with 99mTc glucoheptonate scintigraphy Vesicoureteric reflux in children: prediction with color Doppler imaging Voiding cystourethrography: the initial radiologic study in children with urinary tract infection Sample Size Average Age Minimum Age Maximum Age Female, % Comments Cross-sectional Good y 12 y 83.7 Initial or recurrent UTI Cohort Fair wk 13 mo Cohort 0.5 Fair y 76.0 Bacteriologic UTI; half asymptomatic Cohort 0.5 Good wk 13 y 91.0 Symptomatic outpatients with UTI Cohort: 0.9 Good Median 3 y 3 d 19 y 79.0 Chart review, does not specify diagnostic test 11 mo site Cohort: 0.72 Good ureters 26 d 9 y 74.0 Radiographic studies at small diagnostic test hospital; history of IUTI Case series Fair wk 6 y? Review of records of children with UTI and urography Kangarloo et al 163 Urinary tract infection in infants and children Case series Fair d 18 y? Radiology department; review of evaluated by ultrasound patients with UTI Isdale 164 The role of radiology in urinary tract Cohort 0.66 Fair y 65.0 Radiology department review of infection in children y 3 y urograms, most UTI; may be a y 5 y fairly selected population y 7 y y 14 y McDonagh and Bell 165 Urinary tract infection in a peripheral paediatric unit Cohort 0.5 Fair y 75.0 Review chart study Tsai 166 Vesico-ureteral reflux in infants and children Cohort Fair Infants and?? 54.0 Referred to urologic clinics children Gross and Infection does not cause reflux Cohort Good y Radiology department review Lebowitz wk y of charts Bisset et al 71 Urography and voiding cystourethrography: findings in girls with urinary tract Case series Good y 1 mo 18 y Radiology department review of charts infection Strife et al 168 Nuclear cystography and renal sonography: Cohort Fair y 1 mo 18 y Review of charts (urograms) findings in girls with urinary tract infection Tam et al 169 Role of renal ultrasonography (RUS) and Clinical trial Fair y 1 mo 11 y 33.0 Confirmed UTI micturating cystourethrogram (MCU) in the assessment of vesico-ureteric reflux (VUR) in children and infants with urinary tract infection (UTI) Principi et al 170 Radiological investigations and first Cross-sectional Good d 8 y 67.8 First symptomatic UTI symptomatic urinary tract infection in infants and children y 6y 66.0

21 Downloaded from by guest on August 16, of 60 TABLE 5. Continued Author Title Design Score Grade Prevalence of VUR, % Tapaneya-Olarn et al 171 Marild et al 172 Hodson and Wilson 173 Rushton et al 174 Alon et al 175 Johnson et al 176 Hellstrom et al 52 Honkinen et al 68 Melis et al 177 Bergstrom et al 178 Sample Size Average Age Minimum Age Maximum Age Female, % Comments Genitourinary tract anomalies in Thai children with urinary tract infection Case series Good ? 0 15 y 61.0 First UTI Fever, bacteriuria and concomitant disease in Cohort 0.5 Fair mo 6 y 75.0 Prospective study; inpatients and children with urinary tract infection outpatients with UTI were actively surveyed Natural story of chronic pyelonephritic Cross-sectional 0.33 Poor y Retrospective study based on scarring radiology findings Renal scarring following reflux and Cohort 0.62 Fair kidneys 3.5 y 1.5 y 15 y 66.0 Prevalence among kidneys; nonreflux pyelonephritis in children: therefore, may be evaluation with 99 Tc-dimercaptosuccinic overestimated acid scintigraphy Ultrasonography in the radiologic evaluation Cohort 1 Good y 2 wk 12 y 81.4 Documented UTI, inpatients and of children with urinary tract infection outpatients Renal ultrasound evaluation of urinary tract Cohort 0.54 Fair infections in children Voiding cystourethrography as a predictor of Cohort 0.91 Good mo 2 mo 6 y 74.0 Febrile first documented UTI reflux nephropathy in children with urinary-tract infection Ultrasonography as a screening procedure in Cohort 0.75 Fair ???? Symptomatic UTI children with urinary tract infection Involvement of the renal parenchyma in acute urinary tract infection: the contribution of 99m Tc dimercaptosuccinic acid scan Symptomatic urinary tract infection in boys in the first year of life with special reference to scar formation Cohort (retrospective) 0.45 Fair wk 16 y 61.0 Inpatients from pediatric hospital Cohort 0.5 Fair mo 12 mo 0.0 First UTI, in boys, inpatients Gleeson and Imaging in urinary tract infection Cohort Hospitalized patients; outpatients Gordon also? Rickwood et al 179 Kunin et al 180 Current imaging of childhood urinary infections: prospective survey Urinary tract infection in school children: an epidemiologic, clinical and laboratory study Cross-sectional y 41.0 Symptomatic UTI, emergency and outpatients Cohort 1 Good X 5 y 19 y School children, mostly asymptomatic Kunin 181 Urinary tract infections in children Review Good y 5 y Preschool girls Jequier et al 153 The value of ultrasonography as a screening procedure in a first-documented urinary tract infection in children Cross-sectional 0.66 Fair d 15 y 50.0 First UTI, inpatients and outpatients Hoberman et al 182 Oral vs intravenous therapy for acute pyelonephritis in children Prospective cohort Good mo 24 mo?? Emergency department; abstract only

22 Fig 7. The prevalence of VUR as a function of study size. The variation in reported prevalence of VUR decreases among studies of larger size. A prevalence between 20% and 40% is typical of larger studies. Fig 8. The prevalence of VUR as a function of patient age. The prevalence of VUR reported in 54 studies of UTI in children as a function of the average age of the patients in the study is plotted. In A, the line is a smoothing spline ( 100) fit to the data. In B, the line is a third-order polynomial fit to the data. The studies are weighted by sample size. presumptive oral antibiotic therapy for the infant with suspected UTI before culture results are available? From the data presented subsequently in this report, it may be reasonable to conclude the following. 1) Single-dose to 3-day therapy is not as effective as therapy of 7 days or longer (perhaps because of more rapid metabolism of antimicrobials in children), but that the minimal acceptable duration of therapy has not been demonstrated. 2) Cotrimoxazole appears to be superior to amoxicillin for presumptive antibiotic therapy of UTI, but local antibiotic susceptibility patterns should ultimately dictate the antibiotic choice. Duration of Therapy Several studies have compared treatment of pediatric UTI with varying durations of therapy (Table 4). The data have been analyzed in two ways. First, studies that directly compared different durations of therapy were examined (Table 4, A). Then, data were pooled by antibiotic and duration of therapy, and the pooled values were compared (Table 4, B). None of the studies of duration of therapy compared 7 days with 10 days. In seven studies with 10 comparisons between long duration (7 to 10 days) and short duration (one dose to 3 days), 8 of 10 comparisons showed better results with an attributable improvement in outcome of 5% to 21% When the data were pooled by agent and duration, no discernible differences were found in initial cure or relapse among one-dose, 3-day, and 10-day courses of amoxicillin. However, single-dose cotrimoxazole was 10% less effective than 1-, 3-, 7-, or 22 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

23 TABLE 6. Prevalence of Urinary Tract Abnormality Among Patients With UTI Type of Urinary Tract Abnormality Prevalence of Abnormality Among Patients With UTI, % Age of Study Subjects Sample Size Reference VUR 21 8 mo 86 Ginsburg and McCracken 4 VUR 73 1 y 131 Farnsworth et al 126 Any abnormality 26 Infants 39 Elzouki et al 93 Any abnormality y 21 Burbige et al 133 VUR y 35 Buys et al 18 VUR 54 3 y 303 Jodal 66 Any abnormality y 4 Burbige et al 133 Any abnormality 22 3 mo 12 y 99 Madrigal et al 58 VUR 45 8 mo, female 31 Ginsburg and McCracken 4 VUR 7 8 mo, male 55 Ginsburg and McCracken 4 Any abnormality 41 1 y, male 17 Burbige et al 133 Abnormal VCUG y 83 Nolan et al 60 Any abnormality y, male 17 Cohen 49 VUR 39 2 mo 12 y, First 41 Hashemi 119 Symptomatic UTI VUR y 452 Jodal 66 VUR 36 4 mo 17 y 104 Wientzen et al 55 Any abnormality mo 11 y 20 Bailey and Abbott 120 VUR y 572 McKerrow et al 3 VUR y 94 Majd et al 125 For all studies of infants 3 y day therapy. Differences among the latter regimens were not discernible. Agent The data pooled by agent and duration of therapy were used to compare amoxicillin and cotrimoxazole. For therapies of one dose, 3 to 4 days, or 10 days, cotrimoxazole consistently shows better cure rates (4% to 42%). Data comparing parenteral and oral therapy were not found. However, intramuscular ceftriaxone (one dose) 62 or gentamicin (10 days) 63 was 100% effective in resolving UTI in children in whom oral therapy had failed. No data are available that clarify the role of oral vs parenteral therapy for bacteremia in association with UTI. Drawing on analyses of unsuspected bacteremia in children without UTI, parenteral antibiotic therapy is 95% effective in clearing bacteremia. 64 Prevalence of Urinary Tract Abnormalities UTI in young children is a marker for abnormalities of the urinary tract. By far, the most common abnormality is VUR, which may be present with different degrees of severity that are graded I to V according to whether the reflux reaches the kidney and the degree of dilation of the collecting system. 65 The grade of VUR is important because it determines the likelihood of detecting VUR on radiologic evaluation and the probability of renal damage, hypertension, or renal failure. VUR The Subcommittee identified 77 studies that reported the prevalence of VUR among children with UTI (Table 5). The range of reported values is wide. However, examination of the graph of the prevalence of VUR plotted against the sample size (Fig 7) suggests that the variation is primarily attributable to small samples. As the sample size grows, the prevalence reported converges at 30% to 40%. The prevalence appears to decrease with age. Figure 8, A and B, presents plots of reported prevalence of VUR by the average age of subjects in each of 24 studies. One outlier, a study with an average age of about 7 years and a prevalence of 73% was excluded. Figure 8, A, shows a model fit to the data in which each point is weighted by the sample size of the study it represents. The resultant graph shows a decline in the prevalence of VUR with increasing age. The intercept is 45% and the slope is 3% per year of age. Comparable graphs of prevalence of VUR by maximum or minimum age do not show a consistent relationship. Specific studies of the relationship between age and prevalence of VUR show similar results. For example, Buys et al 18 reported a 68% prevalence among boys younger than 1 year and 25% among boys 1 to 3 years. In another study of boys, Cohen 49 found some type of abnormality in 76% of boys younger than 10 years ( 54% of these were VUR) and 15% in boys older than 10 years. In a populationbased study, Jodal 66 showed a peak prevalence of VUR among girls 1 to 3 years of age and a rapid drop-off (perhaps by half) by age 5. In a much smaller study, Shah and associates 67 found VUR in 100% of 9 boys younger than 1 year of age with a UTI and in 74% of 34 boys 1 to 5 years of age. This relationship was fitted to a third-degree polynomial (Fig 8, A) and a spline ( 1; Fig 8, B). Although the data are insufficient to define a particular functional relationship, they suggest a decline in the prevalence of VUR with age that seems to be most rapid during the first year of life. It levels off somewhat between 1 and 5 years of age, then drops off again after age 5. When studies of children younger than 3 years were pooled, the prevalence was 50% (Table 6). Downloaded from by guest on August 16, of 60

24 TABLE 7. Distribution of Grades of Reflux Among Children With VUR Author Title VUR Grade Distribution, % Study Size (Children) Hashemi 119 Recurrent urinary tract infection I II IV 40.7 Decter et al 183 Vesicoureteral reflux in boys I II 32.8 III 23.4 IV 17.8 V 15.4 Farnsworth et al 126 The detection of reflux nephropathy in infants by 99m I, II kidneys technetium dimercaptosuccinic acid studies III 47.4 IV, V 21.1 Chao et al 85 Vesicoureteric reflux and renal scarring in children: a local I 13.6 perspective II 17.3 III 23.5 IV 38.3 V 7.4 Holland et al 184 Relation of urinary tract infection and vesicoureteral reflux II to scars: follow-up of thirty-eight patients III 56.0 IV 21.0 V 6.0 Lanning et al 139 Prediction of vesico-ureteral reflux children from I 13.7 intravenous urography films II 67.4 III 14.7 IV 1.1 V 3.2 Cremin 140 Observations on vesico-ureteric reflux and intrarenal I reflux: a review and survey material II 29.0 III 41.0 Whyte et al 141 A protocol for the investigation of infants with urinary I tract infection II 41.0 III 34.5 IV 5.0 Drew and Acton 144 Radiological findings in newborn infants with urinary I infection II 7.3 III 51.2 IV 34.1 Verber and Serial 99mTc dimercaptosuccinic acid (DMSA) scans after I Meller 149 urinary infections presenting before the age of 5 years II 37.0 III 47.0 Mok and White 152 The value of radiological investigation in paediatric I urinary tract infection II-A 26.2 II-B 40.9 III 11.4 IV 8.7 Middleton and The lack of correlation between upper tract changes on I Nixon 154 excretory urography and significant vesicoureteral reflux II 38.0 III 38.0 IV 3.0 Kenda et al 157 Renal ultrasound and excretory urography in infants and I young children with urinary tract infection II 76.3 III 15.0 IV 3.8 Total Johnson et al 159 Identification of children requiring radiologic evaluation I 16.7 for urinary infection II 66.7 III 16.7 Total Josifidis et al 185 Inflammatory cell infiltrate in distal ureteral segments I from patients with reflux II 36.6 III 26.1 IV 20.9 V 4.7 McDonagh and Urinary tract infection in a peripheral paediatric unit I Bell 165 II 45.7 III 31.4 Tsai 166 Vesico-ureteral reflux in infants and children I II 34.1 III 9.3 IV 2.9 Bisset et al 71 Urography and voiding cystourethrography: findings in I girls with urinary tract infection II 17.2 III 57.8 IV 1.6 V of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

25 TABLE 7. Continued Author Title VUR Grade Distribution, % Study Size (Children) Strife et al 168 Nuclear cystography and renal sonography: findings in girls I 3.2 with urinary tract infection II 64.5 III 29.0 IV 3.2 Total Aperia et al 186 Correlation between kidney parenchymal area and renal I kidneys function in vesicoureteral reflux of different degrees II 11.0 III 52.0 Principi et al 170 Radiological investigations and first symptomatic urinary II 9.2 (170) tract infection in infants and children III 81.6 IV 9.2 Marild et al 172 Fever, bacteriuria and concomitant disease in children with I, II urinary tract infection III or 23.4 more Shanon et al 187 Evaluation of renal scars by technetium-labeled I 9.0 dimercaptosuccinic acid scan, intravenous urography, and II 26.0 ultrasonography: a comparative study III 59.0 IV 6.0 Skoog et al 188 A nonsurgical approach to the management of primary I ureters vesicoureteral reflux II 54.1 III 31.6 IV 5.7 V 1.9 Edwards et al 189 Disappearance of vesicoureteric reflux during long-term I ureters prophylaxis of urinary tract infection in children II 19.5 III 50.6 IV 14.3 Bellinger and Vesicoureteral reflux: a comparison of non-surgical and I units Duckett 190 surgical management II 37.4 III 24.8 IV 24.3 V 4.8 Honkinen et al 68 Ultrasonography as a screening procedure in children with I II urinary tract infection III V 14.1 Melis et al 177 Involvement of the renal parenchyma in acute urinary tract I infection: the contribution of 99m Tc dimercaptosuccinic II 18.6 acid scan III 32.3 IV 26.4 V 3.7 Rickwood et al 179 Current imaging of childhood urinary infections: prospective I (179) survey II 43.6 III 16.4 IV 16.4 V 1.8 Hoberman et al 182 Oral vs. intravenous therapy for acute pyelonephritis in I children II 41.4 III 23.0 IV 5.7 Wolfish et al 78 Prevalence of hypertension in children with primary I vesicoureteral reflux II 45.9 III 31.5 IV 8.2 V 2.1 VUR indicates vesicoureteral reflux. The grade of VUR is shown in Table 7. Not all studies report the grade of VUR using the international grading system. In other studies, a three-grade system is usually used. Based on the descriptions of the grading systems in these studies, grade I corresponds to grades I and II in the international system, grade II to grade III in the international system, and grade III to grades IV and V in the international system. For this analysis, grades of VUR were grouped into low grade (grades I and II) and high grade (grades III to V). This grouping reduces the precision of the analysis slightly because higher grade reflux is easier to detect with ultrasonography and poses a greater risk of subsequent renal damage than do the lower grades. However, these effects were represented in this model, making this a more detailed analysis than has been reported previously. Some studies grouped patients in a similar manner, but grade III VUR was variably grouped as high grade or low grade. For classification of results, the classification used in the articles was (by necessity) used in this analysis. Pooling the data from Table 7 gives a 51.1% prevalence of low-grade (grades I to II) VUR among patients with VUR. Tests for VUR The Subcommittee identified the gold standard test for detecting VUR as the VCUG or RCG. These studies have, by definition, 100% sensitivity and Downloaded from by guest on August 16, of 60

26 specificity. The Subcommittee also believed that renal ultrasonography or intravenous pyelography should be performed to identify obstructions or other structural renal abnormalities. VCUG and RCG are expensive and invasive. Data were collected on the sensitivity and specificity of renal ultrasonography alone in the detection of VUR. Overall, renal ultrasonography has poor sensitivity (30% to 62%) and good specificity (85% to 100%) for VUR. 68,69 The sensitivity is better, however, for highgrade VUR than for low-grade VUR (82% to 100% vs 14% to 30%). 68,70 The Subcommittee members believed that renal ultrasonography in young infants was less reliable than this. However, data supporting this point were not found. Progressive Renal Damage The evidence that links the presence of VUR to important clinical outcomes can only be assembled in a piecemeal way. The data link VUR to renal scarring in the presence of recurrent infection, and renal scarring is associated with subsequent hypertension and ESRD (Fig 9). The data support this model indirectly. However, there are no longitudinal data that link directly the presence of VUR in infants with febrile UTI and normal kidneys to the subsequent development of hypertension or ESRD. Therefore, it is difficult to quantify the strength of the relationship or the risk to such patients. The following discussion reviews evidence supporting each step in the hypothesized progression to renal damage. Reflux and Scarring The data demonstrate an association between VUR and subsequent renal scarring. More than 48 references reviewed reported renal scarring at rates between 1% and 40% in association with febrile UTI and VUR. Higher grades of VUR are associated with higher risk of scar progression. Patients with highgrade VUR are four to six times more likely to have scarring than those with low-grade VUR and eight to 10 times as likely as those without VUR. 3,66,71,72 In one study of 84 consecutive children 2 to 70 months of age with their first recognized febrile UTI, 52 the presence of VUR was 80% sensitive and 74% specific in predicting subsequent scarring in a follow-up period of 2 years or more. Of those with VUR, 30% had progressive renal scarring. Of those without VUR, only 4% did. Recurrent Infections and Scarring The association of VUR with renal scarring seems to be mediated through recurrent symptomatic infections. The association between recurrent bouts of febrile UTI and the risk of renal scarring in one study followed an exponential curve (Fig 10). 66 Patients with no VUR or low-grade VUR and patients with no recurrences of UTI are at low risk for renal scarring. Thus, prophylactic antibiotic treatment of patients with VUR to prevent recurrences or surgical treatment to prevent VUR would be expected to prevent renal scarring. ESRD and Hypertension Retrospective examination of the causes of ESRD in registries of patients with renal failure shows that in 36% (of 9250 patients), the cause of ESRD is obstructive uropathy, renal hypoplasia or dysplasia, pyelonephritis, or a combination of these. 1 Unfortunately, it is not possible to determine which patients originally had normal kidneys in whom disease progressed to ESRD because of VUR and recurrent infection. In the North American Renal Transplant Cooperative Study, the fraction of transplant recipients with reflux nephropathy is 102/2033, or 5%. Patients with pyelonephritis or interstitial nephritis make up another 2% of transplant recipients. 2 Most cohort studies to quantify the risk of ESRD and hypertension among patients with renal scarring and VUR are based on highly selected patients in whom extensive scarring already has occurred. Long-term studies show that ESRD develops in 3% to 10% of these patients. 3,73 75 In addition, 10% may require nephrectomy, and 0.4% renal transplantation. 3 One study followed women from their first UTI in childhood and found that abnormal renal function could be documented in 21% of those with severe scarring. 76 However, this study also had a selected population and did not provide data on VUR. The rate of hypertension in these and similar studies varies between 0% and 50%. 3,73,75 78 It is apparently lowest in those with low-grade VUR 79 and those with the least scarring. 77 However, the quality of the studies relating VUR nephropathy with ESRD and hypertension was rated poor, and quantification of the relationship is weak. One study 78 identified retrospectively a cohort of children 1 month to 16 years of age with VUR and measured blood pressure levels 5 months to 21 years (average, 9.6 years) after VUR was identified. There was an increase in the blood pressure level associated with increasing grades of VUR. However, none of the patients had hypertension. Effectiveness of Prophylactic Antimicrobials and Surgical Correction Ultimately the value of identifying VUR depends on the potential to prevent its long-term consequences. As Fig 9 illustrates, this depends on reduc- Fig 9. A model of the theoretical relationship of VUR to the development of ESRD and hypertension. 26 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

27 Fig 10. Predicted and observed relationships between recurrent UTI and renal scarring. The plot of the risk of renal scarring as a function of the number of UTIs illustrates the close match between the data observed and what would be predicted by an exponential model. ing recurrent infections with antibiotic prophylaxis or eliminating VUR surgically. The efficacy of these procedures is not well documented because controlled studies have not been performed. Studies in which patients receiving antibiotic prophylaxis are compared with those not taking antimicrobials suggest a 50% effectiveness whether comparing rates of reinfection 73,79 83 or progression of scarring. 24,51 Cost Data Cost data were derived from literature where available, the accounting department of the University of North Carolina (UNC) Hospital, and the physicians fee schedule from the UNC Physicians and Associates. Estimates used in the decision model are given below. UA and Culture Based on the cost data from the UNC Hospital, the cost of a urine culture is $21.53 (charge, $26.00). The cost of a UA is $6.77 (charge, $15.00). Treatment The cost of short-term treatment of UTI varies substantially depending on the treatment chosen. Standard oral therapy, such as amoxicillin or trimethoprim sulfamethoxazole, costs about $10 for a course. Newer, broad-spectrum oral therapy costs about $40 for a 10-day course. If parenteral therapy, such as intramuscular ceftriaxone, is given, the cost of the drug and the injection may be $125. Complications of Therapy For the analysis, only complications requiring a return visit to the physician were considered. This visit would cost a $50 clinic fee, plus a $50 professional fee, for a total of $100. Death attributable to anaphylaxis is rare. The additional cost of this complication was not added. Cost of Urosepsis It is assumed that sepsis that does not clear spontaneously or with antibiotic therapy will require hospital admission for intravenous antibiotic therapy at a cost of $ Imaging Evaluation The two following imaging strategies were considered: 1) a full work-up, including renal ultrasonography and VCUG, and 2) renal ultrasonography alone. The cost of renal ultrasonography includes the hospital cost of $104 and the physician fee of $200, for a total of $304. The cost of the VCUG is the hospital cost of $123 plus the physician fee of $200, totaling $323. Thus, the full work-up costs $627. Cost of Treatment of VUR The estimated cost of antibiotic prophylaxis was based on low-dose nitrofurantoin. The weekly cost was $6 for an average of 3 years. The total is $1040. It was assumed that the cost of ureteral reimplantation surgery was similar. Complications of VUR Patients with VUR are at increased risk for recurrent UTI, 3,75,84,85 at least until the VUR resolves. The period the child is at risk was assumed to be 3 years. The cost of these recurrences was based on the average cost of a clinic visit related to a diagnosis of UTI or pyelonephritis in infants at UNC, $134, plus the physician fee of $70. This was multiplied by three, the average number of infections expected over 3 years, 84 for a total of $612. The cost of ESRD was derived from data in previous analyses. 86,87 Based on a 10-year period, including 10 years of dialysis or a year in which transplantation occurs followed by 8 years with a functioning graft, followed by 1 year of a failed graft, the cost of ESRD is $ The cost of managing severe hypertension and its complications was estimated at $ based on $2000 per year for 50 years. 88,89 Downloaded from by guest on August 16, of 60

28 Analysis of the Decision Model Using data extracted from the literature as described in Evidence Tables, probabilities and costs were inserted into the decision tree. Table 8 shows the baseline estimates for the variables in the model. Using these estimates, three types of analysis were conducted. First, a risk analysis was performed to determine the average cost and frequency of outcomes expected with each of four strategies. Next, a cost-effectiveness analysis was used to determine the incremental cost per major clinical outcome averted by the strategies. Finally, sensitivity and threshold analyses were performed to examine alternative strategies for evaluation and management of UTI. Risk Analysis Two risk analyses were performed. The first examined the costs and clinical outcomes expected with different strategies for making the diagnosis of UTI. The second compared alternative strategies for imaging the urinary tract of patients with UTI. Diagnosis of UTI The risk analysis of diagnostic strategies examines two anchor states. The first, treat all, is presumptive antibiotic therapy for occult infection without TABLE 8. Variables and Baseline Estimates Used in the Risk and Cost-effectiveness Analyses Diagnosis of UTI Prevalence of UTI 0.05 Sensitivity of culture 1.0 Specificity of culture 1.0 Cost of culture $ Sensitivity of bag culture 1.0 Specificity of bag culture 0.7 Cost of bag culture $ Sensitivity of urinalysis 0.92 Specificity of urinalysis 0.70 Cost of urinalysis $ 6.77 Treatment of UTI Cost of antimicrobials for UTI $ Probability of treatment complication 0.10 Cost of treatment complication $100 Risk of death due to complication Risk of sepsis with UTI 0.09 Efficacy of treatment 0.95 Cost of sepsis $ Probability sepsis will resolve 0.7 Probability of death from sepsis 0.10 Probability of VUR 0.40 Probability VUR is high grade 0.41 Imaging evaluation Sensitivity of renal ultrasonography for low-grade VUR 0.14 Sensitivity of renal ultrasonography for high-grade 0.82 VUR Specificity of renal ultrasonography for VUR 1.0 Cost of renal ultrasonography $304 Sensitivity of full imaging evaluation 1.00 Specificity of full imaging evaluation 1.00 Cost of full imaging evaluation $637 Complications of abnormalities Risk of scarring without VUR 0.07 Risk of scarring, low-grade VUR 0.13 Risk of scarring, high-grade VUR 0.53 Risk of hypertension after scarring 0.20 Cost of hypertension $ Risk of ESRD after scarring 0.05 Cost of ESRD $ testing. The second, observe, is clinical observation without testing or treatment. Neither of these anchor strategies involves subsequent imaging of the urinary tract. Three testing strategies are evaluated. The first is the gold standard, culture of urine specimens obtained by suprapubic tap or transurethral catheter. The second is using a culture of the urine specimen obtained from the urine bag. Culture of bag urine specimens has 100% sensitivity and 70% specificity in the baseline analysis. The third strategy uses the cheaper but less reliable reagent strip as a test for UTI. A positive LE test result, a positive nitrite test result, or both, is considered a positive test result. The sensitivity and specificity of this strategy are 92% and 70%, respectively, based on median values given in Table 3, C. All three testing strategies include antibiotic therapy and imaging of the urinary tract of patients with positive test results. The results of the risk analysis are presented as the number of outcomes expected per infants treated by using each strategy (Table 9). To observe patients without testing or treatment is the least expensive strategy. However, it results in inferior clinical outcomes, including death and hospitalization from urosepsis, hypertension, and ESRD. Presumptive treatment of all infants without testing costs slightly more than observing, but prevents hospitalization and death from urosepsis. Under the treat all strategy, it is impossible to select patients for imaging, and it is unreasonably expensive to image the urinary tracts of all patients (see Cost-effectiveness Analysis ). Therefore, no patient in the treat all strategy undergoes imaging evaluation. As a result, there is no improvement in the rates of hypertension or ESRD. Using culture of urine specimens obtained by catheterization or tap offers the lowest risk of death, because all children at risk for urosepsis are identified and there are no unnecessary treatments or treatment-related deaths. Moreover, because all children with UTI are identified for imaging evaluation, this strategy minimizes the risk of hypertension and ESRD. Using a culture of bag urine specimens as a criterion for the diagnosis of UTI also identifies correctly all children with UTI. However, its poor specificity also results in many false-positive results. As a consequence, there are slightly more deaths (3 per million) attributable to unnecessary antibiotic treatment and many more imaging work-ups. This means an additional $47.2 million per febrile infants with no improvement in clinical outcomes. Using LE and nitrite as diagnostic criteria for UTI leaves a small number of UTIs undiagnosed and results in times as many imaging work-ups compared with a culture of urine specimens obtained by catheterization or tap. The result is poorer clinical outcomes at greater expense despite the lower cost of UA. A fourth diagnostic strategy also was evaluated that used a full UA (reagent strip and microscopy) as an initial diagnostic test and treated any positive UA component as a positive result. A positive result would lead to presumptive treatment. However, 28 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

29 TABLE 9. Risk Analysis of Diagnostic Strategies Anticipated Costs and Outcomes for a Cohort of Patients Treated Using Each Strategy Strategy Cost (in millions) Untreated UTI Imaging Work-ups Hypertension ESRD Deaths Treat all $ Culture transurethral $ catheterization or suprapubic bladder tap Culture bag urine $ LE or nitrite $ UA, culture positives $ Observe $ positive results would be confirmed by a culture of urine specimens obtained by tap or catheterization before imaging was performed. This strategy has a sensitivity of virtually 100% and a specificity of 60% 36,38,39 for making a treatment decision. Because positive results are confirmed with a culture of urine specimens obtained by catheterization or tap, the specificity is 100% for imaging. The cost of testing is higher for positive results because UA and culture are performed. Also, the false-positive results lead to more unnecessary treatment and the resulting costs and complications. However, there is a cost saving for patients with negative results of the UA because the UA costs less than the culture. Compared with a culture of specimens from all patients, there is a small net decrease in cost using UA followed by a culture of positive results. Moreover, this strategy has the advantage of allowing immediate treatment of patients at risk of UTI. The benefit of early treatment is difficult to quantify, but evidence suggests it reduces the risk of renal scarring. 51 Although this strategy appears to be nearly as effective as (or perhaps more than) the culture of urine specimens obtained by catheterization or tap, its effectiveness depends on the accuracy of the urine microscopy. As noted above, the accuracy of urine microscopy is highly variable and apparently depends on the presence of an on-site technician. In many settings, this may be impossible or so expensive as to offset the benefits. Imaging Strategies Three imaging alternatives were evaluated by risk analysis (Table 10). The first strategy was renal ultrasonography and VCUG. The second was renal ultrasonography alone, and the third was no imaging evaluation at all. The total cost associated with each strategy includes the cost of the imaging studies, the cost of treating abnormalities identified, and the cost of any complications incurred. Together, renal ultrasonography and VCUG will identify all cases of renal abnormalities. Renal ultrasonography alone detects 42% of all abnormalities. However, most abnormalities (87%) missed by renal ultrasonography alone are low-grade VUR, which carries a lower risk of renal scarring. As a result, the differences in clinical outcomes (cases of hypertension and ESRD) are smaller between renal ultrasonography alone and the full evaluation. Cost-effectiveness Analysis Cost-effectiveness analysis was used to quantify the trade-offs between cost and clinical effect when moving from one clinical strategy to another. When one strategy offers a better clinical effect at a lower cost, it is said to be a dominant strategy. However, in most cases, the strategy with better clinical effect also has a higher cost. Cost-effectiveness analysis depicts the additional cost per unit of improvement in clinical effect. For this analysis, the units of effect were defined as cases of death, ESRD, or hypertension prevented. Strategies were compared using the incremental (or marginal) cost-effectiveness ratio, ie, the difference in cost among strategies divided by the difference in effect. The mathematical term is as follows: Cost b Cost a Effect b Effect a. Table 11 gives the alternative strategies in order of increasing cost. The first column indicates the strategy, the second column shows the additional cases (per patients) prevented compared with the preceding strategy; and the third column presents the additional cost per case prevented above the preceding strategy. Diagnosis of UTI The least expensive strategy for the diagnosis of UTI is to do nothing. This also is the least effective strategy. By comparison, treating all febrile 2-month to 2-year-olds for UTI without diagnostic testing or urinary tract imaging improves clinical effect at a TABLE 10. Risk Analysis of Alternative Strategies for Imaging the Urinary Tracts of Infants With UTI Expected Cost of Clinical Outcomes Expected for 1000 Patients Treated Under Each Strategy Imaging Strategy Cost (in millions) Abnormalities Identified Cases of Hypertension Renal ultrasonography and VCUG $ Renal ultrasonography alone $ No evaluation $ Cases of ESRD Downloaded from by guest on August 16, of 60

30 TABLE 11. Marginal Cost-effectiveness of Strategies for Diagnosis and Treatment of UTI Strategy Additional Cases Prevented (Per Patients) Cost per Additional Case Prevented Do nothing NA NA Treat all 10 $ Dipstick, confirm positives with culture of 20 $ suprapubic bladder tap or transurethral catheterization Culture all, suprapubic bladder tap or transurethral catheterization 2.5 $ cost of $ per death prevented. However, it does not prevent ESRD or hypertension. As an alternative, one could obtain a dipstick UA on all patients, culturing specimens from those for whom the results of UA were positive. Because UA costs less than culture, this strategy has the potential to save money. However, because UA does not have perfect sensitivity (Table 3), a few cases will be missed. In addition, patients for whom the results of UA are positive will incur the costs of UA and culture. To evaluate this strategy, a new branch was added to the decision tree. The new branch is a dipstick UA. If results are positive, it is linked to the test branch; if results are negative, it is linked to the observe branch. Positive results involve the cost of the UA plus culture; negative results, only the cost of the UA. This strategy prevents an additional two cases of death or serious complication per at a cost of $ per case. Culturing catheterization or tap urine specimens on all patients and then treating and imaging the urinary tracts of all patients with positive results is the most effective and most expensive strategy. It prevents an additional 2.5 cases of death or serious complication per over culture-confirmed positive dipstick results at an additional cost of $ per case prevented. Compared with the no testing strategy, culturing specimens from all patients prevents three cases of death or serious complication per at a cost of $ per case prevented. The optimal strategy depends on the decisionmaker s willingness to pay for each additional case prevented. For example, if that willingness to pay is between $ and $ , then the positive results of the dipstick confirmed by culture is the best strategy. Culturing specimens from all patients will prevent a few additional cases, but the cost to prevent each of these additional cases exceeds the decision-maker s willingness to pay. If the decisionmaker is willing to pay $ to prevent a case of death or serious complication, then culturing specimens from all patients is the right strategy. Imaging Strategies The cost-effectiveness of the alternative imaging strategies also was calculated (Table 12). The least expensive alternative is to perform no evaluation. Renal ultrasonography alone will prevent almost three cases of ESRD or hypertension per 1000 studies done at a cost of $ per case prevented. A VCUG prevents an additional one case of ESRD or hypertension per 1000 studies over renal ultrasonography at a cost of $ per case. Again, the optimal strategy depends on the decision-maker s willingness to pay for each additional case prevented. For example, if that willingness to pay is between $ and $ , then renal ultrasonography alone is the best strategy. A VCUG will prevent a few additional cases, but the cost to prevent each of these additional cases exceeds the decision-maker s willingness to pay. If the decision maker is willing to pay $ to prevent a case, then renal ultrasonography and VCUG is the right strategy. Sensitivity and Threshold Analysis Choosing one alternative over another from the risk analyses shown in Tables 9 and 10 involves striking a balance between the cost of an intervention and the improvement in clinical outcomes. When comparing alternatives, if one alternative provides better clinical outcomes at lower costs, it is the dominant alternative and is the obvious choice. However, in most circumstances, choosing an alternative requires a trade-off between costs and clinical benefit. For example, obtaining a urine specimen for culture by catheterization or tap on all febrile infants, treating those with positive cultures, and imaging their urinary tracts with VCUG and renal ultrasonography improves clinical outcome but at a substantially higher cost than doing none of these evaluations. To select the optimal alternative and, moreover, to identify different clinical circumstances in which different alternatives may be better, it is first necessary to make explicit the trade-off between costs and clin- TABLE 12. Marginal Effect and Cost-effectiveness of Strategies for Imaging the Urinary Tracts of Children With UTI Strategy Additional Cases Prevented (Per 1000 Studied) Cost Per Additional Case Prevented Do nothing NA NA Renal ultrasonography alone 2.8 $ Renal ultrasonography and VCUG 1.0 $ of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

31 ical outcomes. This means identifying a willingness to pay for each untoward clinical outcome avoided. For the following analyses, a value of $ was placed on each case of ESRD or hypertension prevented. This figure is based loosely on the lifetime productivity of a healthy, young adult. 90 Once this cost is assigned to each untoward clinical outcome, it is possible to use the threshold method of decisionmaking. 91 The threshold approach to decision-making involves changing the value of a variable in the decision analysis to determine the value at which one alternative becomes too expensive and another would be preferred. In the case of UTI, if the prior probability of UTI is sufficiently high, it costs $ to prevent a case of ESRD or hypertension by screening all febrile children. However, if the probability that a particular patient has a UTI is sufficiently low, the yield of a urine culture will be extremely low and a positive result of a UA will almost certainly be a false-positive. Under these circumstances, a strategy involving the evaluation of this child s urinary tract would cost $ per case of ESRD or hypertension prevented. Threshold analysis identifies the threshold probability of UTI above which evaluation would be cost-effective and below which it would not. A number of threshold analyses follow. Prevalence of UTI and Prevalence of VUR Because fever without an obvious cause is common in pediatric practice, culturing the urine of all febrile 2-month to 2-year-old children represents a substantial investment. The Subcommittee was interested in determining whether there were some clinical subpopulations in which the prevalence of UTI was low enough that culture was unnecessary. A threshold analysis was used to examine this question. Figure 11 illustrates a two-way sensitivity analysis. The x-axis shows the prevalence of UTI between 0 and 1, and the y-axis shows the prevalence of VUR among children with UTI. The decision tree was evaluated for all combinations of the prevalence of UTI and VUR. The graph in Fig 11 is divided into two parts by a threshold line. Above and to the right of the line, culturing urine specimens from all febrile infants prevents ESRD and hypertension at a cost of $ per case prevented. Below and to the left of this threshold line, the cost to prevent a case of ESRD or hypertension would be $ per case. Also plotted on the graph are the prevalence of UTI and VUR for febrile females younger than 1 year, females older than 1 year, males younger than 1 year, males older than 1 year, males younger than 1 year and circumcised, and males older than 1 year and circumcised (Table 2). Among circumcised males older than 1 year, the prevalence of UTI and VUR fall well below the threshold line. This implies that in circumcised males older than 1 year, obtaining a urine specimen for culture with the objective of preventing ESRD or hypertension is too expensive, and no evaluation of the urine is the preferred alternative. Circumcised males younger than 1 year fall only slightly below and to the left of the threshold line. In this group, the cost-effectiveness of obtaining a urine specimen for culture is borderline. Cost of Culturing Urine Obtained by Urine Bag Many practitioners prefer to culture urine specimens obtained by urine bag rather than by transurethral catheter or suprapubic tap because the urine Fig 11. Threshold analysis, prevalence of UTI, and prevalence of VUR. This graph plots the combination of prevalence values for UTI and VUR at which evaluation for UTI (as described in the practice parameter) would be cost-effective (see text). Also plotted are the predicted prevalence values for subpopulations at risk Downloaded from by guest on August 16, of 60

32 bag is less invasive. However, culture of a urine specimen obtained by bag has low specificity. When the prevalence of UTI is low, as it is in febrile infants, the result is a large number of false-positive urine cultures. False-positive cultures lead to unnecessary antibiotic treatment and urinary tract evaluation. The result is additional costs with no clinical benefit. To examine these additional costs, the difference in costs between a strategy involving urine specimens obtained by catheterization or tap and a strategy involving specimens from bag urine was calculated at different levels of specificity for the urine bag. The result is plotted in Fig 12. In Fig 12, the x-axis shows that the specificity of a culture of specimens from bag urine varied between 0% and 100%. The y-axis shows the difference in costs between strategies that involve the culture of urine specimens obtained by bag and strategies involving the culture of urine specimens obtained by catheterization or tap. As the specificity of the culture of bag urine varies from 0% to 100%, the additional costs varies between $1600 and $0. The shaded region shows the range of specificities reported for the culture of specimens from bag urine. At the low end, for a specificity of 14%, the cost per patient of obtaining urine by bag rather than by catheterization or tap is $1340 per person. At the high end, for a specificity of 84%, the additional cost of obtaining urine specimens by bag instead of by catheterization or tap is $293 per patient. At the baseline estimate of 70% specificity, the additional cost of the strategy of culturing urine specimens obtained by bag rather than by catheterization is $429. These results imply that culturing urine specimens from bag urine in this setting can only be justified if one is willing to pay between $293 and $1340 per patient to use a urine bag rather than to obtain urine specimens by catheterization or tap. Sensitivity and Specificity for UA As an alternative to obtaining urine specimens for culture from all febrile children between 2 months and 2 years of age, one could use a UA to make the diagnosis of UTI. As noted previously, a carefully performed UA has high sensitivity and specificity. Two-way sensitivity analysis was used to determine the minimal sensitivity and specificity that would be necessary to justify the use of UA rather than culture. The results are shown in Fig 6. Figure 6 plots the false-positive rate (1 minus specificity) on the x-axis and the true-positive rate (sensitivity) on the y-axis. All the reported test characteristics for various components and combination of components of the UA are plotted on this graph (see Tests for Urinary Tract Infection ). For all combinations of sensitivity and specificity, the decision tree was reevaluated to determine whether the UA or a culture of specimens from all patients was the most cost-effective strategy. The result is a threshold line shown in the top left corner of the Fig 6. If the sensitivity and specificity of the UA falls above and to the left of this threshold line, it would be preferred to urine culture. If the sensitivity and specificity fall below and to the right of this line, presumptive culture is preferred. Of all the sensitivities and specificities reported, only one study that used a combination of dipstick and microscopy achieved this level of sensitivity and specificity. This study had an on-site laboratory technician in the clinic who processed the urine specimens within 1 hour of collection. These results imply that a test must have a sensitivity 92% and a specificity 99% to be preferred over urine culture. This level of sensitivity and specificity is unlikely to be obtained in most clinical settings. Alternatively, several studies demonstrated that combinations of LE, nitrite, microscopy of fresh Fig 12. Costs of relying on a culture of urine collected by bag. This graph plots the expected cost per patient predicted from relying on urine cultures with varying degrees of specificity. 32 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

33 Fig 13. Threshold analysis of the sensitivity of renal ultrasonography alone for high-grade and lowgrade VUR. Also shown (dots) are reported sensitivities from the literature. For values above and to the right of the threshold line, ultrasonography alone would be a cost-effective strategy (see text). Fig 14. Threshold analysis of the risk of scar progression given low-grade VUR and the risk of scar progression given high-grade VUR. The dot shows the baseline estimate used in the model. Evaluation for UTI, according to the practice parameter, is cost-effective for values above and to the right of the threshold line. urine, or a combination of these, in which any abnormality constituted a positive test result, yielded a sensitivity of 92% (Fig 6). If one of these tests were used to rule out UTI, and culture of urine specimens obtained by catheterization or tap were used to confirm UTI in positive results, the requisite sensitivity and specificity would be obtained. Probability of UTI and Urinary Tract Imaging The decision to image the urinary tracts of infants with documented UTI presumes that the diagnosis of UTI is certain. If an imperfect test (eg, using a bag urine specimen) is used to make the diagnosis of UTI, a substantial number of these patients in fact may not Downloaded from by guest on August 16, of 60

34 Fig 15. Two-way sensitivity analysis of the probability of hypertension and the probability of ESRD. Evaluation for UTI, according to the practice parameter, is cost-effective for values above and to the right of the threshold line. The baseline estimate used in the model and the range of reported values also are shown. have had a UTI and, therefore, the yield of the imaging will be lower. Threshold analysis was used to determine the minimal probability of UTI that justified a full imaging evaluation. The analysis indicates that if the probability of UTI is 49%, imaging becomes too expensive. Bayes s theorem shows that among patients with a prevalence of UTI that is 5%, those who have a positive urine culture obtained by bag have a probability (positive predictive value) of UTI that is 15%, well below 49%. This implies that if the best evidence of the UTI available in a given patient is a positive culture of urine obtained by bag, additional imaging of the urinary tract is not justified. APPENDIX 1. Terms Used in Literature Search Group I: Child at risk Key Words General terms Children (2 to 5 y) Infants (2 mo to 2 y) UTI/Urinary tract infection Fever Bacteriuria Other terms Age Race Sex Socioeconomic status Circumcision Urban/rural Group I specific terms Voiding Dysfunction Urgency Frequency Hesitancy Dysuria Examination Presentation Urinary incontinence Abdominal pain Failure to thrive (Foul-smelling urine) Cystitis Pyelonephritis Sepsis (Setting) Hospital Emergency department Pediatrician Urologist Family practitioner Group II: Specimen Key Words General terms Children (2 to 5 y) Infants (2 mo to 2 y) UTI/urinary tract infection Fever Bacteriuria Other terms Age Race Sex Socioeconomic status Circumcision Urban/rural Group II specific terms Diagnosis Interpretation Results Presentation Testing Screening Urinalysis Specimen Criteria Collection Methods 34 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

35 APPENDIX 1. Continued (Setting) Hospital Office Emergency department Pediatrician Urologist Family practitioner Group III: Treatment of Acute UTI Key Words General terms Children (2 to 5 y) Infants (2 mo to 2 y) UTI/Urinary tract infection Fever Bacteriuria Other terms Age Race Sex Socioeconomic status Circumcision Urban/rural Group III specific terms Treatment Therapy Upper UTI Lower UTI Hospitalization Oral Parenteral Antibiotic Alternatives (Setting) Hospital Office Emergency department Pediatrician Urologist Family practice Diagnosis Differences/versus Group IV: Risk assessment Key Words General terms Children (2 to 5 y) Infants (2 mo to 2 y) UTI/Urinary tract infection Fever Bacteriuria Other terms Age Race Sex Socioeconomic status Circumcision Urban/rural Group IV specific terms Imaging Ultrasound Urography Cystography Radionuclide Renography Cystourethrography Radiography GU System Reflux VUR Obstruction Nephropathy Abnormalities Bladder Kidney Ureter (Setting) Hospital Office Emergency department Pediatrician Urologist Family practice Downloaded from by guest on August 16, of 60

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56 Sensitivity of Renal Ultrasonography for VUR Because VCUG is invasive and expensive, a threshold analysis was used to explore the possible use of renal ultrasonography alone in evaluating the urinary tracts of children with UTI. Renal ultrasonography has low sensitivity for low-grade VUR, but relatively higher sensitivity for high-grade VUR. Figure 13 plots sensitivity of renal ultrasonography for low-grade VUR on the x-axis and sensitivity of renal ultrasonography for high-grade VUR on the y-axis. For values that plot above and to the right of the threshold line on this graph, renal ultrasonography alone would be the preferred strategy. For values that fall below and to the left of the threshold line, a combination of renal ultrasonography and VCUG would be preferred. Also plotted on this graph are reported values of the sensitivity of renal ultrasonography for low-grade and high-grade VUR. Based on the professional opinion of the UTI Subcommittee, a sensitivity of 14% for low-grade VUR and 82% for high-grade VUR (the lower point in Fig 13) is a better reflection of the situation in children 2 months to 2 years of age. This implies that renal ultrasonography alone is an inadequate imaging evaluation for infants with UTI. Risk of Hypertension and ESRD The weakest probability estimates in the present analysis relate to the risk of ESRD and hypertension among patients who have progressive renal scarring attributable to VUR. Two-way sensitivity analysis was used to determine the effect of varying these estimates on the results of the analysis. Figure 15 plots the probability of hypertension on the x-axis and the probability of ESRD on the y-axis. For values below and to the left of the threshold line shown, it is not cost-effective to obtain a urine specimen for culture from all children to prevent ESRD or hypertension caused by progressive renal scarring. For values above and to the right of the threshold line, culturing urine specimens from all febrile infants is cost-effective. The baseline point estimates of these probabilities are shown, as is the range of values found in our review of the literature (shaded area). Our best estimate of the risk of hypertension and ESRD justifies culturing urine specimens from febrile infants as a strategy to prevent these complications. However, the quality of evidence about the future risks of ESRD and hypertension among infants with UTI later found to have VUR is tenuous at best. This is an area that needs additional investigation. Risk of Renal Scarring With UTI One area of relative uncertainty, in which quality data are lacking, is the risk of scarring in undetected or untreated VUR. This risk is higher for children with high-grade VUR than for those with low-grade VUR. Threshold analysis was used to explore how this risk of scarring affects the decision to culture urine specimens from all children 2 months to 2 years of age with fever and no obvious cause for the fever. Figure 14 plots the risk of scar progression given low-grade VUR on the x-axis and the risk of scar progression given high-grade VUR on the y-axis. For values that plot above and to the right of the threshold line, culture of urine specimens from all febrile infants is the preferred strategy. For values that plot below and to the left of the threshold line, no urine culture is the preferred strategy. The baseline estimates used in the analysis, 14% for low-grade VUR and 53% for high-grade VUR, are plotted on the graph. The risk of scarring because of untreated VUR seems to be high enough to justify culturing specimens from all febrile infants. RECOMMENDATIONS Who Should Be Evaluated for UTI? Under the assumptions of the analysis, all febrile children between the ages of 2 months and 24 months with no obvious cause of infection should be evaluated for UTI, with the exception of circumcised males older than 12 months. Minimal Test Characteristics of Diagnosis of UTI To be as cost-effective as a culture of a urine specimen obtained by transurethral catheter or suprapubic tap, a test must have a sensitivity of at least 92% and a specificity of at least 99%. With the possible exception of a complete UA performed within 1 hour of urine collection by an on-site laboratory technician, no other test meets these criteria. Performing a dipstick UA and obtaining a urine specimen by catheterization or tap for culture from patients with a positive LE or nitrite test result is nearly as effective and slightly less costly than culturing specimens from all febrile children. 56 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

57 Treatment of UTI The data suggest that short-term treatment of UTI should not be for 7 days. The data do not support treatment for 14 days if an appropriate clinical response is observed. There are no data comparing intravenous with oral administration of medications. Evaluation of the Urinary Tract Available data support the imaging evaluation of the urinary tracts of all 2- to 24-month-olds with their first documented UTI. Imaging should include VCUG and renal ultrasonography. The method for documenting the UTI must yield a positive predictive value of at least 49% to justify the evaluation. Culture of a urine specimen obtained by bag does not meet this criterion unless the previous probability of a UTI is 22%. REFERENCES 1. Loirat C, Ehrich JH, Geerlings W, et al. Report on the management of renal failure in children in Europe, XXIII, Nephrol Dial Transplant. 1994;9: Supplement 2. McEnery P, Alexander SR, Sullivan K, Tejani A. Renal transplantation in children and adolescents: the 1992 annual report of the North American Renal Transplant Cooperative Study. Pediatr Nephrol. 1993; 7: McKerrow W, Davidson-Lamb N, Jones PF. Urinary tract infection in children. Br Med J (Clin Res Educ). 1984;289: Ginsberg CM, McCracken GH Jr. Urinary tract infections in young infants. Pediatrics. 1982;69: Bonadio WA, Smith DS, Madagame E, Machi J, Kini N. Escherichia coli bacteremia in children: a review of 91 cases in 10 years. Am J Dis Child. 1991;145: Diament MJ. Is ultrasound screening for urinary tract infection cost effective? Pediatr Radiol. 1988;18: Verber IG, Meller ST. Development of renal scars after acute nephronia in childhood: a study of sequential DMSA scans. Contrib Nephrol. 1990;79: Kramer MS, Tange SM, Drummond KN, Mills EL. Urine testing in young febrile children: a risk benefit analysis. J Pediatr. 1994;125: Hoberman A, Wald E. Data, Sackett D, Haynes R, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston, MA: Little Brown & Co Inc; Bonadio W. Urine culturing technique in febrile infants. Pediatr Emerg Care. 1987;3: Hoberman A, Chao HP, Keller DM, Hickey R, Davis HW, Ellis D. Prevalence of urinary tract infection in febrile infants. J Pediatr. 1993; 123: Roberts K, Charney E, Sweren RJ, et al. Urinary tract infection in infants with unexplained fever: a collaborative study. J Pediatr. 1983; 103: Bauchner H, Philipp B, Dashefsky B, Klein JO. Prevalence of bacteriuria in febrile children. Pediatr Infect Dis J. 1987;6: North A Jr. Bacteriuria in children with acute febrile illnesses. J Pediatr. 1963;63: Baker MO, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med. 1993;329: Kramer MS, Tange MS, Mills EL, Ciampi A, Bernstein ML, Drummond KN. Role of the complete blood count in detecting occult focal bacterial infection in the young febrile child. J Clin Epidemiol. 1993;46: Buys H, Pead L, Hallett R, Maskell R. Suprapubic aspiration under ultrasound guidance in children with fever of undiagnosed cause. Br Med J. 1994;308: Pylkkanen J, Vilska J, Koskimies O. Diagnostic value of symptoms and clean-voided urine specimen in childhood urinary tract infection. Acta Paediatr Scand. 1979;68: McIntyre PB, Gray SV, Vance JC. Unsuspected bacterial infections in febrile convulsions. Med J Aust. 1990;152: Siegel S, Seigel B, Sokoloff BZ, et al. Urinary infection in infants and preschool children: five year follow-up. Am J Dis Child. 1980;134: Pryles CV, Luders D. The bacteriology of the urine in infants and children with gastroenteritis. Pediatrics. 1961;: Hoberman A, Chao HP, Keller DM, Hickey R, Davis HW, Ellis D. Prevalence of urinary tract infection in febrile infants. J Pediatr. 1993; 123: Shimada D, Matsui T, Ogino T, Ikoma F. New development and progression of renal scarring in children with primary VUR. Int Urol Nephrol. 1989;21: Hoekelman RA. Is screening urinalysis worthwhile in asymptomatic pediatric patients? Pediatr Ann. 1994;23: Wiswell TE, Smith FR, Bass JW. Decreased incidence of urinary tract infections in circumcised male infants. Pediatrics. 1985;75: Wiswell TE, Roscelli JD. Corroborative evidence for the decreased incidence of urinary tract infections in circumcised male infants. Pediatrics. 1986;78: Wiswell TE, Hachey WE. Urinary tract infections and the uncircumcised state: an update. Clin Pediatr (Phila). 1993;32: Lerner GR. Urinary tract infections in children. Pediatr Ann. 1994;23: 463, Spach DH, Stapleton AE, Stamm WE. Lack of circumcision increases the risk of urinary tract infection in young men. JAMA. 1992;267: Pfaller M, Ringenberg B, Rames L, Hegeman J, Koontz F. The usefulness of screening tests for pyuria in combination with culture in the diagnosis of urinary tract infection. Microbiol Infect Dis. 1987;6: Wiggelinkhuizen J, Maytham D, Hanslo DH. Dipstick screening for urinary tract infection. S Afr Med J. 1988;74: Hoberman A, Wald ER, Reynolds EA, Penchansky L, Charron M. Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever. J Pediatr. 1994;124: Weinberg AG, Gan VN. Urine screen for bacteriuria in symptomatic pediatric outpatients. Pediatr Infect Dis J. 1991;10: Littlewood JM, Jacobs SI, Ramsden CH. Comparison between microscopical examination of unstained deposits of urine and quantitative culture. Arch Dis Child. 1977;52: Lohr JA, Portilla MG, Geuder TG, Dunn ML, Dudley SM. Making a presumptive diagnosis of urinary tract infection by using a urinalysis performed in an on-site laboratory. J Pediatr. 1993;122: Kierkegaard H, Feldt-Rasmussen U, Horder M, Andersen HJ, Jorgensen PJ. Falsely negative urinary leucocyte counts due to delayed examination. Scand J Clin Lab Invest. 1980;40: Lam CN, Bremner AD, Maxwell JD, Murphy AV, Low WJ. Pyuria and bacteriuria. Arch Dis Child. 1967;42: Houston IB. Pus cell and bacterial counts in the diagnosis of urinary tract infections in childhood. Arch Dis Child. 1963;38: Hoberman A, Wald ER, Penchansky L, Reynolds EA, Young S. Enhanced urinalysis as a screening test for urinary tract infection. Pediatrics. 1993;91: Tahirovic H, Pasic M. A modified nitrite test as a screening test for significant bacteriuria. Eur J Pediatr. 1988;147: Bixler-Forell E, Bertram MA, Bruckner DA. Clinical evaluation of three rapid methods for the detection of significant bacteriuria. J Clin Microbiol. 1985;22: Djojohadipringgo R, Abdul Hamid RH, Thahir S, Karim A, Darsono I. Bladder puncture in newborns: a bacteriological study. Paediatr Indones. 1976;16: Leong YY, Tan KW. Bladder aspiration for diagnosis of urinary tract infection in infants and young children. J Singapore Paediatr Soc. 1976; 18: Pryles CV, Atkin MD, Morse TS, Welch KJ. Comparative bacteriologic study of urine obtained from children by percutaneous suprapubic aspiration of the bladder and by catheter. Pediatrics. 1959;24: Sorensen K, Lose G, Nathan E. Urinary tract infections and diurnal incontinence in girls. Eur J Pediatr. 1988;148: Taylor CM, White RH. The feasibility of screening preschool children for urinary tract infection using dipslides. Int J Pediatr Nephrol. 1983;4: Shannon FT, Sepp E, Rose GR. The diagnosis of bacteriuria by bladder puncture in infancy and childhood. Aust Paediatr J. 1969;5: Cohen M. The first urinary tract infection in male children. Am J Dis Child. 1976;130: Barbin GK, Thorley JD, Reinarz JA. Simplified microscopy for rapid detection of significant bacteriuria in random urine specimens. J Clin Microbiol. 1978;7: Winter AL, Hardy BE, Alton DJ, Arbus GS, Churchill BM. Acquired renal scars in children. J Urol. 1983;129: Hellstrom M, Jacobsson B, Marild S, Jodal U. Voiding cystourethrography as a predictor of reflux nephropathy in children with urinarytract infection. AJR Am J Roentgenol. 1989;152: Marshall R, Teele DW, Klein JO. Unsuspected bacteremia due to Downloaded from by guest on August 16, of 60

58 Haemophilus influenzae: outcome in children not initially admitted to hospital. J Pediatr. 1979;95: Wald ER, Minkowski JM. Bacteremia in children. South Med J. 1980; 73: Wientzen R, McCracken GH Jr, Petruska ML, Swinson SG, Kaijser B, Hanson LA. Localization and therapy of urinary tract infections of childhood. Pediatrics. 1979;63: Short-term treatment of acute urinary tract infection in girls. Scand J Infect Dis. 1991;23: Kosnadi L, Widayat R, Wastoro D, Yunanto A, Gunawan R. Treatment of acute urinary tract infection in children with pipemidic acid. Paediatr Indones. 1989;29: Madrigal G, Odio CM, Mohs E, Guevara J, McCracken GH Jr. Single dose antibiotic therapy is not as effective as conventional regimen for management of acute urinary tract infections in children. Pediatr Infect Dis J. 1988;7: Stahl G, Topf P, Fleisher GR, Norman ME, Rosenblum HW, Gruskin AB. Single-dose treatment of uncomplicated urinary tract infections in children. Ann Emerg Med. 1984;13: Nolan T, Lubitz L, Oberklaid F. Single dose trimethoprim for urinary tract infection. Arch Dis Child. 1989;64: Pitt WR, Dyer SA, McNee JL, Burke JR. Single dose trimethoprim sulphamethoxazole treatment of symptomatic urinary infection. Arch Dis Child. 1982;57: Dagan R, Phillip M, Watemberg NM, Kassis I. Outpatient treatment of serious community-acquired pediatric infections using once daily intramuscular ceftriaxone. Pediatr Infect Dis J. 1987;6: Principi N, Gervasoni A, Reali E, Tagliabue P. Treatment of urinary tract infections in children with a single daily dose of gentamicin. Helv Paediatr Acta. 1977;32: Baraff L, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Pediatrics. 1993;92: Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen- Mobius TE. International system of radiographic grading of vesicoureteric reflux: international reflux study in children. Pediatr Radiol. 1985;15: Jodal U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am. 1987;1: Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child. 1978;53: Honkinen O, Ruuskanen O, Rikalainen H, Makinen EO, Valimaki I. Ultrasonography as a screening procedure in children with urinary tract infection. Pediatr Infect Dis. 1986;5: Stokland E, Hellstrom M, Hansson S, Jodal U, Oden A, Jacobsson B. Reliability of ultrasonography in the identification of reflux nephropathy in children. Br Med J. 1994;309: Alon U, Berant M, Pery M. Intravenous pyelography in children with urinary tract infection and vesicoureteral reflux. Pediatrics. 1989;83: Bisset GS III, Strife JL, Dunbar JS. Urography and voiding cystourethrography: findings in girls with urinary tract infection. AJR Am J Roentgenol. 1987;148: Gleeson FV, Gordon I. Imaging in urinary tract infection. Arch Dis Child. 1991;66: Mihindukulasuriya JC, Maskell R, Polak A. A study of fifty-eight patients with renal scarring associated with urinary tract infections. Q J Med. 1980;49: Williams DI, Kenawi MM. The prognosis of pelviureteric obstruction in childhood: a review of 190 cases. Eur Urol. 1976;2: Jacobson SH, Eklof O, Lins LE, Wikstad I, Winberg J. Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood: a 27-year follow up. Pediatr Nephrol. 1992;6: Warshaw BL. Nephrotic syndrome in children. Pediatr Ann. 1994;23: Heale WF. Hypertension and reflux nephropathy. Aust Paediatr J. 1977;13: Wolfish NM, Delbrouck NF, Shanon A, Matzinger MA, Stenstrom R, McLaine PN. Prevalence of hypertension in children with primary vesicoureteral reflux. J Pediatr. 1993;123: Welch TR, Forbes PA, Drummond KN, Nogrady MB. Recurrent urinary tract infection in girls: group with lower tract findings and a benign course. Arch Dis Child. 1976;51: Marget W, Belohradski BH, Nickel B. Comparison of long- and shortterm treatment of recurrent urinary tract infection. Infection. 1979;7): S394 S Lohr JA, Nunley DH, Howards SS, Ford RF. Prevention of recurrent urinary tract infections in girls. Pediatrics. 1977;59: Parks D, Layne P, Uri J, Ziv D, Bass S. Ceftizoxime: clinical evaluation of efficacy and safety in the USA. J Antimicrob Chemother. 1982;10: Jodal U, Larsson P, Hansson S, Bauer CA. Pivmecillinam in long-term prophylaxis to girls with recurrent urinary tract infections. Scand J Infect Dis. 1989;21: Carlsen NL, Hesselbjerg U, Glenting P. Comparison of long-term, low-dose pivmecillinam and nitrofurantoin in the control of recurrent urinary tract infection in children: an open, randomized, cross-over study. J Antimicrob Chemother. 1985;16: Chao SM, Saw AH, Tan CL. Vesicoureteric reflux and renal scarring in children: a local perspective. Ann Acad Med Singapore. 1991;20: Eggers P. Comparison of treatment costs between dialysis and transplantation. Semin Nephrol. 1992;12: Karlberg I. Cost analysis of alternative treatments in end-stage renal disease. Transplant Proc. 1992;24: Menard J, Cornu P, Day M. Cost of hypertension treatment and the price of health. J Hum Hypertens. 1992;6: Rovira J, Badia X, Pardell H. Cost of hypertension in Spain. J Hum Hypertens. 1992;6: Yadin O. Hematuria in children. Pediatr Ann. 1994;23: Ettenger RB. The evaluation of the child with proteinuria. Pediatr Ann. 1994;23: Siegel SR, Sokoloff B, Seigel B. Asymptomatic and symptomatic urinary tract infection in infancy. Am J Dis Child. 1973;125: Elzouki AY, Mir NA, Jeswal OP. Symptomatic urinary tract infection in pediatric patients: a developmental aspect. Int J Pediatr Nephrol. 1985;6: Kunin CM, DeGroot JE. Sensitivity of a nitrite indicator strip method in detecting bacteriuria in preschool girls. Pediatrics. 1977;60: Lowe PA. Chemical screening and prediction of bacteriuria: a new approach. Med Lab Sci. 1985;42: Corman LI, Foshee WS, Kotchmar GS, Harbison RW. Simplified urinary microscopy to detect significant bacteriuria. Pediatrics. 1982;70: Vickers D, Ahmad T, Coulthard MG. Diagnosis of urinary tract infection in children: fresh urine microscopy or culture? Lancet. 1991;338: Pryles CV, Luders D, Alkan MK. A comparative study of bacterial cultures and colony counts in paired specimens of urine obtained by catheter versus voiding from normal infants and infants with urinary tract infection. Pediatrics. 1961;27: Goldsmith BM, Campos JM. Comparison of urine dipstick, microscopy, and culture for the detection of bacteriuria in children. Clin Pediatr (Phila). 1990;29: Marsik FJ, Owens D, Lewandowski J. Use of the leukocyte esterase and nitrite tests to determine the need for culturing urine specimens from a pediatric and adolescent population. Diagn Microbiol Infect Dis. 1986; 4: Aronson AS, Gustafson B, Svenningsen NW. Combined suprapubic aspiration and clean-voided urine examination in infants and children. Acta Paediatr Scand. 1973;62: Boreland PC, Stoker M. Dipstick analysis for screening of paediatric urine. J Clin Pathol. 1986;39: Cannon H Jr, Goetz ES, Hamoudi AC, Marcon MJ. Rapid screening and microbiologic processing of pediatric urine specimens. Diagn Microbiol Infect Dis. 1986;4: Goossens H, De Mol P, Hall M, Butzer JP. Prevalence of asymptomatic bacteriuria and comparison between different screening methods for its detection in infants. Eur J Epidemiol. 1985;1: Hoberman A, Wald ER, Reynolds EA, Charron M, Penchansky L. Cost-effective screening for urinary tract infection (UTI) in young children with fever. Arch Pediatr Adolesc Med. 1994;148. Abstract 106. Sinaniotis CA, Haratsaris MN, Papadatos CJ. Nitrite indicator strip test for bacteriuria. Lancet. 1978;1: Shapiro ED, Wald ER. Single-dose amoxicillin treatment of urinary tract infections. J Pediatr. 1981;99: Avner ED, Ingelfinger JR, Herrin JR, et al. Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections. J Pediatr. 1983;102: Sullivan TD, Ellerstein NS, Neter E. The effects of ampicillin and trimethoprim/sulfamethoxazole on the periurethral flora of children with urinary tract infection. Infection. 1980;8:S339 S Ellerstein NS, Sullivan TD, Baliah T, Neter E. Trimethoprim/ sulfamethoxazole and ampicillin in the treatment of acute urinary tract infections in children: a double blind study. Pediatrics. 1977;60: Khan AJ, Ubriani RS, Bombach E, Agbayani MM, Ratner H, Evans HE. 58 of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

59 Initial urinary tract infection caused by Proteus mirabilis in infancy and childhood. J Pediatr. 1978;93: Fennell RS, Luengnaruemitchai M, Iravani A, Garin EH, Walker RD, Richard GA. Urinary tract infections in children: effect of short course antibiotic therapy on recurrence rate in children with previous infections. Clin Pediatr (Phila). 1980;19: Rajkumar S, Saxena Y, Rajagopal V, Sierra MF. Trimethoprim in pediatric urinary tract infection. Child Nephrol Urol. 1988;9: Malaka-Zafiriu K, Papadopoulos F, Avgoustidou-Savopoulou P, Papachristos F. Comparison of cefadroxil and ampicillin in the treatment of urinary tract infections in children. Clin Ther. 1984;6: Syriopoulou V, Bitsi M, Theodoridis C, Saroglou I, Krikos X, Tzanetou K. Clinical efficacy of sulbactam/ampicillin in pediatric infections caused by ampicillin-resistant or penicillin-resistant organisms. Rev Infect Dis. 1986;8:S630 S Al Roomi LG, Sutton AM, Cockburn F, McAllister TA. Amoxicillin and clavulanic acid in the treatment of urinary infection. Arch Dis Child. 1984;59: Lohr JA, Hayden GF, Kesler RW, et al. Three-day therapy of lower urinary tract infections with nitrofurantoin macrocrystals: a randomized clinical trial. J Pediatr. 1981;99: Russo RM, Gururaj VJ, Laude TA, Rajkumar SV, Allen JE. The comparative efficacy of cephalexin and sulfisoxazole in acute urinary tract infection in children. Clin Pediatr (Phila). 1977;16: Hashemi G. Recurrent urinary tract infection. Indian J Pediatr. 1985;52: Bailey RR, Abbott GD. Treatment of urinary tract infection with a single dose of trimethoprim sulfamethoxazole. Can Med Assoc J. 1978; 118: Helin I. Short-term treatment of lower urinary tract infections in children with trimethoprim/sulphadiazine. Infection. 1981;9: Howard JB, Howard JE. Trimethoprim sulfamethoxazole vs sulfamethoxazole for acute urinary tract infections in children. Am J Dis Child. 1978;132: Aarbakke J, Opshaug O, Digranes A, Hoylandskjaer A, Fluge G, Fellner H. Clinical effect and pharmacokinetics of trimethoprim sulphadiazine in children with urinary tract infections. Eur J Clin Pharmacol. 1983;24: Khan AJ, Kumar K, Evans HE. Three-day antimicrobial therapy of urinary tract infection. J Pediatr. 1981;99: Majd M, Rushton HG, Jantausch B, Wiedermann BL. Relationship among vesicoureteral reflux, P-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. J Pediatr. 1991;119: Farnsworth RH, Rossleigh MA, Leighton DM, Bass SJ, Rosenberg AR. The detection of reflux nephropathy in infants by 99 m technetium dimercaptosuccinic acid studies. J Urol. 1991;145: Cohen HA, Drucker MM, Vainer S, et al. Post-circumcision urinary tract infection. Clin Pediatr (Phila). 1992;31: Lomberg H, Eden CS. Influence of P blood group phenotype on susceptibility to urinary tract infection. FEMS Microbiol Immunol. 1989; 1: Snodgrass W. Relationship of voiding dysfunction to urinary tract infection and vesicoureteral reflux in children. Urology. 1991;38: de Man P. Bacterial attachment, inflammation and renal scarring in urinary tract infection. Wien Med Wochenschr. 1991;141: Chiu NC, Huang FY, Tsai TC. Urinary tract infections in children. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1989;30: Dickinson JA. Incidence and outcome of symptomatic urinary tract infection in children. Br Med J. 1979;1: Burbige KA, Retik AB, Colodny AH, Bauer SB, Lebowitz R. Urinary tract infection in boys. J Urol. 1984;132: Welch TR, Forbes PA, Drummond KN, Nogrady MB. Recurrent urinary tract infection in girls: group with lower tract findings and a benign course. Arch Dis Child. 1976;51: Newcastle Covert Bacteriuria Research Group. Covert bacteriuria in school girls in Newcastle on Tyne: a 5-year follow-up. Arch Dis Child. 1981;56: Verrier Jones K, Asscher AW, Verrier Jones ER, Mattholie K, Leach K, Thomson GM. Glomerular filtration rate in schoolgirls with covert bacteriuria. Br Med J. 1982;285: Thelle T, Biskjaer. Combined [99 m] Tc DMSA kidney scintigraphy and [131]Hippuran renography in children with urinary tract infections. Acta Paediatr Scand. 1985;74: Tappin DM, Murphy AV, Mocan H, et al. A prospective study of children with first acute symptomatic E coli urinary tract infection. Acta Paediatr Scand. 1989;78: Lanning P, Seppanen U, Huttunen NP, Uhari M. Prediction of vesicoureteral reflux in children from intravenous urography films. Clin Radiol. 1979;30: Cremin BJ. Observations on vesico-ureteric reflux and intrarenal reflux: a review and survey of material. Clin Radiol. 1979;30: Whyte K, Abbott GD, Kennedy JC, Maling TM. A protocol for the investigation of infants and children with urinary tract infection. Clin Radiol. 1988;39: Ben-Ami T, Rozin M, Hertz M. Imaging of children with urinary tract infection: a tailored approach. Clin Radiol. 1989;40: Drachman R, Valevici M, Vardy PA. Excretory urography and cystourethrography in the evaluation of children with urinary tract infection. Clin Pediatr (Phila). 1984;23: Drew JH, Acton CM. Radiological findings in newborn infants with urinary infection. Arch Dis Child. 1976;51: Moncrieff MW, Whitelaw R. Value of cystography in urinary tract infections. Arch Dis Child. 1976;51: Bourchier D, Abbott GD, Maling TM. Radiological abnormalities in infants with urinary tract infections. Arch Dis Child. 1984;59: Verber IG, Strudley MR, Meller ST. 99 mtc dimercaptosuccinic acid (DMSA) scan as first investigation of urinary tract infection. Arch Dis Child. 1988;63: Ring E, Zobel G. Urinary infection and malformations of urinary tract in infancy. Arch Dis Child. 1988;63: Verber IG, Meller ST. Serial 99 m Tc dimercaptosuccinic acid (DMSA) scans after urinary infections presenting before the age of 5 years. Arch Dis Child. 1989;64: Ozen HA, Whitaker RH. Does the severity of presentation in children with vesicoureteric reflux relate to the severity of the disease or the need for operation? Br J Urol. 1987;60: Monahan M, Resnick JS. Urinary tract infections in girls: age at onset and urinary tract abnormalities. Pediatrics. 1978;62: Mok PM, White PR. The value of radiological investigation in paediatric urinary tract infection. Australas Radiol. 1979;23: Jequier S, Forbes PA, Nogrady MB. The value of ultrasonography as a screening procedure in a first-documented urinary tract infection in children. J Ultrasound Med. 1985;4: Middleton AW Jr, Nixon GW. The lack of correlation between upper tract changes on excretory urography and significant vesicoureteral reflux. J Urol. 1980;123: Redman JF, Seibert JJ. The role of excretory urography in the evaluation of girls with urinary tract infection. J Urol. 1984;132: Baker R, Barbaris HT. Comparative results of urological evaluation of children with initial and recurrent urinary tract infection. J Urol. 1976; 116: Kenda R, Kenig T, Silc M, Zupancic Z. Renal ultrasound and excretory urography in infants and young children with urinary tract infection. Pediatr Radiol. 1989;19: Smellie JM, Normand IC, Katz G. Children with urinary infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int. 1981;20: Johnson CE, Shurin PA, Marchant CD, et al. Identification of children requiring radiologic evaluation for urinary infection. Pediatr Infect Dis. 1985;4: Traisman ES, Conway JJ, Traisman HS, et al. The localization of urinary tract infection with 99 mtc glucoheptonate scintigraphy. Pediatr Radiol. 1986;16: Marshall JL, Johnson ND, DeCampo MP. Vesicoureteric reflux in children. Prediction with color Doppler imaging: work in progress. Radiology. 1990;175: Blickman JG, Taylor GA, Lebowitz RL. Voiding cystourethrography: the initial radiologic study in children with urinary tract infection. Radiology. 1985;156: Kangarloo M, Gold RH, Rine RN, Diament MJ, Boechat MI. Urinary tract infection in infants and children evaluated by ultrasound. Radiology. 1985;154: Isdale JM. The role of radiology in urinary tract infection in children. S Afr Med J. 1978;53: McDonagh B, Bell JN. Urinary tract infection in a peripheral paediatric unit. Ir Med J. 1981;74: Tsai T. Vesico-ureteral reflux in infants and children. J Formos Med Assoc. 1979;78: Gross GW, Lebowitz RL. Infection does not cause reflux. AJR Am J Roentgenol. 1981;137: Strife J, Bisset GS III, Kirks DR, et al. Nuclear cystography and renal sonography: findings in girls with urinary tract infection. AJR Am J Roentgenol. 1989;153: Tan SM, Chee T, Tan KP, Cheng HK, Ooi BC. Role of renal ultrasonog- Downloaded from by guest on August 16, of 60

60 raphy (RUS) and micturating cystourethrogram (MCU) in the assessment of vesico-ureteric reflux (UVR) in children and infants with urinary tract infection (UTI). Singapore Med J. 1988;29: Principi A, Gervasoni A, Bellini F. Radiological investigations and the first symptomatic urinary tract infection in infants and children. Acta Paediatr Belg. 1978;31: Tapaneya-Olarn C, Tapaneya-Olarn W, Assadamongkol K. Genitourinary tract anomalies in Thai children with urinary tract infection. J Med Assoc Thai. 1989;72: Marild S, Hellstrom M, Jodal U, Eden CS. Fever, bacteriuria and concomitant disease in children with urinary tract infection. Pediatr Infect Dis J. 1989;8: Hodson C, Wilson S. Natural history of chronic pyelonephritic scarring. Br Med J. 1965;2: Rushton H, Majd M, Jantausch B, Wiedermann BL, Belman AB. Renal scarring following reflux and nonreflux pyelonephritis in children: evaluation with 99 m technetium-dimercaptosuccinic acid scintigraphy. J Urol. 1992;147: Alon U, Pery M, Davidai G, Berant M. Ultrasonography in the radiologic evaluation of children with urinary tract infection. Pediatrics. 1986;78: Johnson CE, DeBaz BP, Shurin PA, DeBartolomeo R. Renal ultrasound evaluation of urinary tract infections in children. Pediatrics. 1986;78: Melis K, Vandevivere J, Hoskens C, Vervaet A, Sand A, Van Acker KJ. Involvement of the renal parenchyma in acute urinary tract infection: the contribution of 99 mtc dimercaptosuccinic acid scan. Eur J Pediatr. 1992;151: Bergstrom T, Jacobsson B, Larson H, Lincoln K, Winberg J. Symptomatic urinary tract infection in boys in the first year of life with special reference to scar formation. Infection. 1973;1: Rickwood A, Carty HM, McKendrick T, et al. Current imaging of childhood urinary infections: prospective survey. Br Med J. 1992;304: Kunin CM, Deutscher R, Paquin A Jr. Urinary tract infection in school children: an epidemiologic, clinical and laboratory study. Medicine. 1964;43: Kunin CM. Urinary tract infections in children. Hosp Pract (Baltimore). 1976;11: Hoberman A, Wald ER, Reynolds EA, Charron M, Penchansky L. Oral vs intravenous therapy for acute pyelonephritis in children 1 24 months. Pediatr Res. 1994;35:143A 183. Decter RM, Roth DR, Gonzales ET Jr. Vesicoureteral reflux in boys. J Urol. 1988;140: Holland NH, Jackson EC, Kazee M, Conrad GR, Ryo UY. Relation of urinary tract infection and vesicoureteral reflux to scars: follow-up of thirty-eight patients. J Pediatr. 1990;116:S65 S Josifidis HT, Khan AR, Montgomery P, Greenfield SP. Inflammatory cell infiltrate in distal ureteral segments from patients with reflux. Urology. 1989;44: Aperia A, Broberger O, Ekengren K, Ericsson NO, Wikstad I. Correlation between kidney parenchymal area and renal function in vesicoureteral reflux of different degrees. Ann Radiol (Paris). 1977;20: Shanon A, Feldman W, McDonald P, et al. Evaluation of renal scars by technetium-labeled dimercaptosuccinic acid scan, intravenous urography, and ultrasonography: a comparative study. J Pediatr. 1992;120: Skoog SJ, Belman AB, Majd M. A nonsurgical approach to the management of primary vesicoureteral reflux. J Urol. 1987;138: Edwards D, Normand IC, Prescod N, Smellie JM. Disappearance of vesicoureteric reflux during long-term prophylaxis of urinary tract infection in children. Br Med J. 1977;2: Bellinger MF, Duckett JW. Vesicoureteral reflux: a comparison of nonsurgical and surgical management. Contrib Nephrol. 1984;39: of 60 AMERICAN ACADEMY Downloaded OF from PEDIATRICS by guest on August 16, 2018

61 Technical Report: Urinary Tract Infections in Febrile Infants and Young Children Stephen M. Downs Pediatrics 1999;103;e54 DOI: /peds e54 Updated Information & Services References Subspecialty Collections Permissions & Licensing Reprints including high resolution figures, can be found at: This article cites 182 articles, 44 of which you can access for free at: This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant sub Genitourinary Disorders s_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Downloaded from by guest on August 16, 2018

62 Technical Report: Urinary Tract Infections in Febrile Infants and Young Children Stephen M. Downs Pediatrics 1999;103;e54 DOI: /peds e54 The online version of this article, along with updated information and services, is located on the World Wide Web at: Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 1999 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Downloaded from by guest on August 16, 2018