URINARY TRACT INFECTION (UTI) IS RELATIVELY common

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1 Urinary tract infections (UTI) are one of the most common and serious infections among pediatric patients in the emergency department. Detection of UTI requires a systematic approach to urine testing and an understanding of the limitations to common screening tests. Proper culturing techniques are essential to the diagnosis. Accurate diagnosis and prompt treatment can reduce morbidity associated with UTIs. Clin Ped Emerg Med 5: Elsevier Inc. All rights reserved. Pediatric Urinary Tract Infection By Richard Bachur, MD BOSTON, MASSACHUSETTS URINARY TRACT INFECTION (UTI) IS RELATIVELY common in children presenting to the emergency department (ED), yet the diagnosis is often elusive. Over the last two decades, pediatric clinicians have developed a better understanding of which children are at risk, the limitations of screening tests, and the factors that lead to long-term morbidity, specifically renal scarring, hypertension, and renal failure. Renal scarring following a febrile UTI has been estimated to occur in 15% to 30%, and most of the scarring occurs in children under 4 years of age. 1-7 In one long-term follow-up study, focal renal scars led to adult hypertension in 23%, end stage renal disease in 10%, and toxemia during pregnancy in 13%. 8 From the perspective of emergency medicine, UTI may present as an acute febrile illness, but the evaluation and treatment need to extend well beyond the ED encounter. Timely diagnosis will limit the risk of renal scarring as well as trigger urologic investigation for vesicoureteral reflux (VUR) and obstructive conditions. Accordingly, this article will focus on which children to evaluate for UTI, how to make an accurate diagnosis, and the initial management of a presumed or proven UTI. From the Division of Emergency Medicine, Children s Hospital Boston, Boston, Massachusetts. Address reprint requests to Richard Bachur, MD, Division of Emergency Medicine, Children s Hospital, 300 Longwood Ave, Boston, MA richard.bachur@childrens. harvard.edu /$ see front matter 2004 Elsevier Inc. All rights reserved. doi: /j.cpem Definitions UTI is a nonspecific term and refers to bacterial invasion into the urologic system. UTI can be considered as two anatomically distinct categories: lower tract infection, including urethritis and cystitis, and upper tract infections, such as ureteritis, pyelitis (upper collecting system), and pyelonephritis (renal parenchyma). In children, elements of the history, physical examination findings, and presence of fever cannot distinguish upper versus lower tract infection. 7,9,10 Based on multiple investigations, three-quarters of children with a febrile UTI have pyelone- 28 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR

2 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR 29 phritis by renal scan 1,9,11-13 ; therefore, children with fever and signs of a UTI are presumed to have pyelonephritis. Therefore, further distinction between lower and upper tract will not be discussed. Diagnosis of UTI Three principles should be followed for correctly identifying patients with UTI: 1. Be suspicious for UTI and screen patients at risk (based on prevalence data and clinical factors); 2. Understand the limitations of screening tests; and 3. Rely on appropriate urine cultures Clinical Presentation Classic symptoms (frequency, dysuria, urgency, hesitancy, incontinence, vomiting, fever, and chills) and signs (fever, suprapubic tenderness, and flank tenderness) are present in older children, but these features are often absent in infants, toddlers, and pre-schoolers. In infants, nonspecific symptoms of poor feeding, irritability, or fever may be combined with emesis or apparent abdominal pain. Fever is often the only sign of UTI by physical examination in young infants. 14,15 Astute parents may recognize dysuria or note malodorous urine. In neonates, UTI may be the etiology for unexplained hyperbilirubinemia or failure to thrive. Among older infants and toddlers, fever is more reliably present and when associated with vomiting, abdominal pain, or urinary retention, a UTI should be suspected. Beyond 2 years of age, when children are also more verbal, more typical symptoms and signs may suggest a UTI; even among these older children, however, dysuria and flank pain are frequently absent even with documented pyelonephritis. 16 Outside infancy, classic UTI symptoms may also be present with vaginitis or urethritis either infectious (candida, herpes, S pyogenes, N gonorrhea, or pinworms) or non-infectious irritation. Similarly, urethral strictures or vaginal or urethral foreign bodies can have UTI-like symptoms. Among children with acute fever and abdominal pain or flank pain, other causes (viral gastroenteritis, bacterial enteritis, appendicitis, pneumonia, or pleuritis) should be considered. Prevalence and the Risk of UTI The true incidence of UTI among children has been difficult to estimate because many large retrospective studies differ in definitions of UTI, study populations, and urine collection methods. The best epidemiologic studies, performed in Scandanavia, estimate the cumulative risk of 1.7% for boys and 7.8% for girls prior to the age of 7 with the greatest risk in the first year of life for both boys and girls Two prospective prevalence studies have specifically investigated febrile children in the ED. Hoberman et al 22 studied 945 infants less than 1 year of age presenting with a temperature 38.3 C, and Shaw et al 14 studied 2411 infants (males 1 year and females 2 years of age) with a temperature 38.5 C. Additionally, we retrospectively reviewed 11,000 medical records of children 2 years of age with a temperature 38.0 C to estimate minimum and maximum prevalence of UTI. 23 The results of these studies are compared in Table 1. As can be seen from the studies, risk factors (ie, based on increased prevalence) include higher fever, white race, female gender, and lack of an alternative source of infection. Younger age is a risk factor, with children 1 year of age being at greatest risk. Figure 1 shows minimum estimates of UTI among febrile children 2 years of age. For highly febrile, white females 1 year of age, the prevalence of UTI has been estimated at 15% to 17% 14,22,23 ; for the same patient who also has no apparent alternative source for fever by examination, the risk of UTI increases to 31%. 14 According to Shaw and Gorelick, 14 two-thirds of febrile infants had another, potential source of fever identified by examination (eg, otitis media, viral syndrome) which highlights the importance of proper screening. Although not considered in these prevalence studies, uncircumcised males have a 5- to 20-fold increased risk in the first year of life ; accordingly, the circumcision rates for different study populations has led to varying estimates of UTI among young male infants. UTI should also be considered in patients with prolonged fever without a source, those with lower abdominal pain, and patients with known urologic abnormalities, including VUR. VUR is the most common urologic problem associated with UTI, being present in 30% to 50% of patients with febrile UTIs 12,27,28 and therefore represents a major risk factor for UTIs. Unfortunately, VUR is often not diagnosed until after a radiologic evaluation (as prompted by the first febrile UTI). Siblings of patients with VUR have an increased risk of VUR, and may lead the clinician to consider an underlying UTI. 29 Lastly, the evaluation of fever in young infants with recognizable viral syndromes such as bronchiolitis has been the subject of several investigations. Although several studies have suggested a

3 30 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR TABLE 1. Prevalence of UTI Hoberman et al 22 N 945 %UTI Shaw et al 14 N 2411 %UTI Bachur et al 23 N a %UTI* Overall Females Males Race White Black Other Fever 39.0 C C Alternative Source of Fever Other potential source of fever No other source of fever White female with fever 39.0 C *Values represent the range (minimum to maximum estimates) of prevalence among all febrile children 2 years of age presenting to a pediatric ED. much lower incidence of UTI among patients with respiratory syncytial virus (RSV) associated bronchiolitis, recent data suggests a slightly lower, but still substantial, risk of UTI 6.5% (95% CI 3.2, 11.7) among febrile patients 60 days of age with RSV bronchiolitis. 34 At this time, very young infants with fever and clinical bronchiolitis should continue to have an evaluation for UTI. Figure 1. Prevalence of UTI among febrile children less than 2 years of age. Data represents minimum estimates of UTI prevalence. 23

4 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR 31 TABLE 2. Definitions of UTI by the Type of Urine Specimen 57 Specimen UTI Probable Contaminant Negative Suprapubic aspiration Any growth Multiple organisms or low colony Pure counts ( 5,000 cfu/ml) of gram positive organisms Known pathogen Bladder catheterization 10,000 cfu/ml Multiple organisms especially if not single Pure dominant pathogen; 10,000 cfu/ml; repeat if clinically indicated Known pathogen Clean void specimen 100,000 cfu/ml 100,000 cfu/ml; multiple pathogens; Pure repeat if clinically indicated Ideally, two separate cultures No growth 1,000 cfu/ml or non-pathogens 20,000 cfu/ml or non-pathogens Abbreviation: cfu, colony forming units; ml, milliliter. Urine Cultures The ultimate diagnosis depends on results of a urine culture. Because many children will receive empiric antibiotics with a suggestive urinalysis, the original, pre-antibiotic, urine culture must be properly collected. Bag specimens are notoriously unreliable for culture with false positive rates as high as 87%. 26,35 Although bag specimens might have utility in children who need surveillance cultures, with an opportunity to repeat a better culture prior to antibiotics if positive, bag specimens should not be used for culture in the ED setting. The most common method for collecting urine for culture in pre-trained infants and toddlers is bladder catheterization. Contamination is still possible given periurethral colonization coupled with the inability to insure sterility when entering the urethra in young females and many young, uncircumcised males. Among children 2 years of age, contamination rates are estimated to be below 5%. 23 Suprapubic aspiration is the most sterile technique for obtaining urine 36,37 but has the disadvantage of lower success rate (46% in single ED study 38 ) and increased invasiveness. Success can be improved with an ultrasound scout immediately before the attempt Midstream, clean-catch specimens are most appropriate in older, toilet-trained children, but are also acceptable when serendipitously collected in infant males. 42 The criteria for culture positivity are dependent on the manner of specimen collection (Table 2). The exact concentration of bacteria required from a bladder catheterization to differentiate infection from bacteriuria has been debated. Patients with low concentrations of bacteria (10,000-50,000 colony forming units (cfu)/ml) are less likely to have associated pyuria, 13,43,44 yet some infants with fever and low concentrations of bacteria have pyelonephritis by renal scan. 45,46 In the setting of pyuria and fever, lower colony counts should be treated as a bona fide UTI; however, if the child has not received antibiotics, repeat culture should be obtained prior to instituting antibiotic therapy. Lower colony counts in the absence of pyuria are highly suspect for bacteriuria rather than a UTI. 13,43 Screening Tests Screening tests for UTI can help decide which patients require a urine culture or which patients should receive empiric antibiotic therapy pending the results of a culture. The most common form of urinalysis (UA) is dipstick testing, which relies on colorimetric assays for white blood cells (leukocyte esterase [LE] as a marker of neutrophils) and nitrite (by product of nitrate degradation by enteric gram-negative bacteria). Dipstick testing is often combined with microscopy of centrifuged urine to determine pyuria (most commonly defined as 5 white blood cells [WBCs]/high power field). Many laboratories use a stepwise approach with microscopy being performed when the dipstick is positive for LE, nitrite, or blood. Gram s stain ( gram stain ) of fresh urine, although labor intensive, can be used

5 32 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR TABLE 3. Test Characteristics of Screening Tests for UTI Screening Test Average Sensitivity Average Specificity Positive Predictive Value* Dipstick LE Nitrite LE or Nitrite LE and Nitrite Microscopy centrifuged urine ( 5 WBC/hpf) Dipstick positive (LE nitrite) or Microscopy positive ( 5 WBC/hpf) Gram stain Enhanced urinalysis Hemocytometer-based pyuria ( 10 WBC/mm3) Positive gram stain or 10 WBC/mm Positive gram stain and 10 WBC/mm NOTE: Values in table are drawn from multiple sources. 10,22,23,54,58,59 A single meta-analysis 58 provides summary estimates for sensitivity and specificity of dipstick testing, microscopy of centrifuged urine, and gram stain. *Positive predictive value (PPV) varies by the population being tested. PPV in table applies to febrile infants 2 years of age. Abbreviations: WBC, white blood cell; hpf, high power field; LE, leukocyte esterase. for screening purposes. Additionally, an enhanced urinalysis has been more recently promoted as a better screening test 47 ; the enhanced UA uses a combination of a hemocytometer-based measure of pyuria ( 10 WBC/mm 3 ) on uncentrifuged urine and a urine gram stain. The test characteristics for dipstick testing, microscopy, gram stain, and the enhanced urinalysis are presented in Table 3. With regard to screening, dipstick testing alone or in combination with microscopic urinalysis appears to be the best strategy. In very young infants, the enhanced UA or a gram stain alone should be considered for their increased sensitivity. Although the enhanced urinalysis has greater sensitivity, hemocytometers and gram stains are currently not practical for office-based testing. Who to screen? Clearly, patients with symptoms or signs referable to the urinary tract should have a urinalysis. Additionally, all young febrile infants 2 months will require a urine culture as part of their standard fever evaluation. Children with risk factors for UTI, as previously discussed, should be screened for UTI. Those patients who have high prior probability should have a urine culture in addition to a screening urinalysis. Patients with lower risk (ie, lower prior probability) can have a screening UA including from a bag specimen; if the screening UA is suggestive of a UTI, an appropriate culture must be obtained. A screening strategy based on the risk factors for UTI and the limitations of screening urinalysis is proposed in Figure 2 for young febrile children. Based on prevalence-determined risk factors, Gorelick and Shaw 48 developed a decision rule to identify which febrile females 2 to 24 months of age should be screened for UTI. The decision rule uses 5 objective factors: (1) a temperature 39.0 C, (2) a fever for 2 days, (3) white race, (4) age 1 year, and (5) the absence of another potential source of fever (eg, upper respiratory infection, otitis media, or pharyngitis). The presence of two or more of these factors has a sensitivity of 95% and a specificity of 31% in identifying females with UTI. More than 2 factors will increase the specificity with an associated decrease in sensitivity (3 risk factors: 66% sensitivity and 77% specificity). A similar rule has not been created for infant males, but unexplained fever, age 6 months, and being uncircumcised are risk factors based on the previously noted data.

6 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR 33 Figure 2. Screening strategy for UTI among febrile children less than 2 years of age. Management of Suspected or Proven UTI Which patients would be treated prior to results of the urine culture? Because the ultimate diagnosis is dependent on a urine culture, ED physicians must interpret the screening tests to make a presumptive diagnosis of UTI. Early initiation of antibiotics has the theoretical advantage of reducing renal scarring, but prescribing antibiotics without proper culture may lead to uncertainty of the diagnosis and unnecessary urologic investigation. For young febrile children with a suggestive UA (minimum of leukocyte esterase by dipstick or pyuria) and older children with symptoms and signs of UTI along with a positive UA (LE or pyuria combined with positive nitrite by dipstick or bacteriuria by gram stain), antibiotics should be prescribed. For older children with mild symptoms or signs and a minimally abnormal UA (ie, low grade pyuria without nitrite or positive gram stain), waiting for the results of the urine culture before instituting antibiotics has advantages. What other tests are necessary in patients with UTIs? Generally, no other tests, other than the UA and urine culture, are required for treating patients with UTIs. As mentioned earlier, gram stain of the urine can help tailor antibiotics but should not delay therapy if it is not readily available. Peripheral WBC counts may suggest some degree of parenchymal involvement, but they do not routinely alter therapy. In studies using renal scans, WBC count, erythrocyte sedimentation rate, and c-reac-

7 34 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR tive protein have had variable correlation with predicting renal parenchymal involvement, and should not be used to guide therapy. 1,7,12 Blood cultures should be considered in ill-appearing patients and young febrile infants with a presumptive UTI. The measurement of blood urea nitrogen and creatinine should be considered for all ill patients, those with significant dehydration or decreased urine output, and patients with known, pre-morbid, alterations in renal function. Examination of the cerebrospinal fluid (CSF) for bacterial meningitis should be considered in neonates and ill-appearing young infants. An aseptic meningitis has also been recognized in 5% to 13% of patients with febrile UTIs ; therefore, examination of the CSF before antibiotics should be considered for all febrile infants 3 months where delayed analysis may raise concern for partially treated bacterial meningitis. Which patients require hospitalization? Most patients with an uncomplicated UTI can be treated as outpatients with oral antibiotics. Patients who are ill-appearing, dehydrated, immunocompromised, or have known renal or urologic abnormalities (other than mild VUR), should be considered for hospitalization. Most infants 3 months of age with a febrile UTI should be admitted for close monitoring; this claim is mostly based on the general fragility of young infants along with high rates of comcommitant bacteremia (21% 1 month of age, 4% overall for 3 months of age). 51 Concerns for meningitis, by physical examination or CSF analysis, should also prompt hospitalization. Which antibiotic is appropriate for initial therapy? Based on the common pathogens, common outpatient antibiotics include amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, cephalexin, and cefixime. Amoxicillin is no longer a good choice because of the high rates of resistance among the enteric gram-negative uropathogens. Quinolones are an excellent choice for UTIs, but are generally not prescribed to pre-pubertal children because of a theoretical concern for cartilage damage. 52,53 For those patients that are hospitalized, monotherapy includes aminoglycosides, cephalosporins (cefotaxime, ceftriaxone, cefazolin), ampicillin/sulbactam, or quinolones in older patients. Young infants are often treated with combinations of ampicillin with an aminoglycoside or third-generation cephalosporin to provide additional coverage for possible bacteremia and broadened coverage to include enterococcus. If a gram stain is performed, antibiotic therapy can be tailored towards the Enterobacteriaciae or enterococcus. A randomized control trial comparing oral cefixime to intravenous cefotaxime showed equal efficacy for short term (time to defervesce) and long term (renal scarring) outcomes in patients with febrile UTIs older than one month of age. 7 Duration of therapy is often debated but the general recommendation is to treat for 7 to 14 days with longer courses for children who are initially more ill or bacteremic. 54 For patients who appear well but have some vomiting or issues of noncompliance, initial therapy can include a parenteral dose of antibiotics. For those patients who are initially hospitalized, the transition to oral antibiotics can occur following clinical improvement. Under parenteral therapy, 68% of patients are afebrile by 24 hours of therapy and 89% are afebrile by 48 hours of therapy. 55 Prolonged fever or ill appearance may suggest resistance or urologic complications such as renal abscess or pyo-hydronephrosis. As a corollary, however, persistent fever for 1 to 2 days following the initiation of outpatient antibiotics in an otherwise well-appearing patient should not demand hospitalization or emergent radiologic studies. All patients should be considered for low dose, antibiotic prophylaxis following treatment and pending results of radiologic investigation. Follow-up For uncomplicated afebrile UTIs in older children, no specific follow-up is indicated other than reviewing culture results to confirm diagnosis and antibiotic sensitivities. For young febrile patients with a presumed UTI, follow-up in 24 to 48 hours is necessary to assess clinical condition, review culture results, and arrange radiologic studies. For patients who have had clinical deterioration (vomiting, dehydration, worsening abdominal or flank pain), persistent high grade fever beyond 48 hours of adequate therapy, or unusually resistant pathogens, admission may be reconsidered. Repeat urine cultures during therapy are generally not necessary to demonstrate effective treatment. Renal scans using dimercaptosuccinic acid (DMSA) are generally not indicated for initial evaluation of UTI, except in rare circumstances where urine culture was never obtained and the diagnosis of pyelonephritis is in doubt. Radiologic evaluation for urologic abnormalities should be performed for all males with a UTI, and all females 5 years of age with a febrile UTI. The timing of the evaluation is debated. 56 Although the choice of studies is debated, the American Academy of Pediatrics practice parameter recommends voiding cystourethrogram and renal ultrasound as primary radiologic evaluation. 54 For patients that are hospitalized, radiologic evaluation can be accomplished

8 PEDIATRIC URINARY TRACT INFECTION / RICHARD BACHUR 35 during the admission. For those treated as outpatients, prophylactic antibiotics should be administered until this evaluation is complete. In summary, UTI is a relatively common infection that can be easily missed in young children. Screening patients at risk, based on prevalence of infection and clinical findings, can lead to proper diagnosis and a reduction in morbidity. The management of UTI is generally straightforward, but follow-up with urologic evaluation is crucial once the diagnosis is made. References 1. Benador D, Benador N, Slosman DO, et al: Cortical scintigraphy in the evaluation of renal parenchymal changes in children with pyelonephritis. J Pediatr 124: 17-20, Gleeson FV, Gordon I: Imaging in urinary tract infection. Arch Dis Child 66: , Kass EJ, Fink-Bennett D, Cacciarelli AA, et al: The sensitivity of renal scintigraphy and sonography in detecting nonobstructive acute pyelonephritis. J Urol 148: , Rushton HG, Majd M: Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J Urol 148: , Berg UB, Johansson SB: Age as a main determinant of renal functional damage in urinary tract infection. Arch Dis Child 58: , Berg UB: Long-term follow-up of renal morphology and function in children with recurrent pyelonephritis. J Urol 148: , Hoberman A, Wald ER, Hickey RW, et al: Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 104:79-86, Jacobson SH, Eklof O, Eriksson CG, et al: Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ 299: , Majd M, Rushton HG: Renal cortical scintigraphy in the diagnosis of acute pyelonephritis. Semin Nucl Med 22:98-111, Hoberman A, Wald ER: Urinary tract infections in young febrile children. Pediatr Infect Dis J 16:11-17, Andrich MP, Majd M: Diagnostic imaging in the evaluation of the first urinary tract infection in infants and young children. Pediatrics 90: , Majd M, Rushton HG, Jantausch B, et al: Relationship among vesicoureteral reflux, P-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. J Pediatr 119: , Hoberman A, Wald ER, Reynolds EA, et al: Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever. J Pediatr 124: , Shaw KN, Gorelick M, McGowan KL, et al: Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics 102:e16, Ginsburg CM, McCracken GH, Jr: Urinary tract infections in young infants. Pediatrics 69: , Hansson S, Martinell J, Stokland E, et al: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 11: , Winberg J, Andersen HJ, Bergstrom T, et al: Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand (Suppl) 252:1-20, Hellstrom A, Hanson E, Hansson S, et al: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66: , Wettergren B, Jodal U, Jonasson G: Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand 74: , Marild S, Jodal U: Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Paediatr Scand 87: , Jakobsson B, Esbjorner E, Hansson S: Minimum incidence and diagnostic rate of first urinary tract infection. Pediatrics 104: , Hoberman A, Chao HP, Keller DM, et al: Prevalence of urinary tract infection in febrile infants. J Pediatr 123:17-23, Bachur R, Harper M: Reliability of the urinalysis for predicting urinary tract infections in young febrile children. Arch Pediatr Adolesc Med 155:60-65, Wiswell TE, Geschke DW: Risks from circumcision during the first month of life compared with those for uncircumcised boys. Pediatrics 83: , American Academy of Pediatrics Task Force on Circumcision: Circumcision policy statement. Pediatrics 103: , Crain EF, Gershel JC: Urinary tract infections in febrile infants younger than 8 weeks of age. Pediatrics 86: , Strife JL, Bisset GS, Kirks DR, et al: Nuclear cystography and renal sonography: findings in girls with urinary tract infection. Am J Roentgenol 153: , Olbing H, Claesson I, Ebel KD, et al: Renal scars and parenchymal thinning in children with vesicoureteral reflux: A 5-year report of the International Reflux Study in Children (European branch). J Urol 148: , Van den Abbeele AD, Treves ST, Lebowitz RL, et al: Vesicoureteral reflux in asymptomatic siblings of patients with known reflux: Radionuclide cystography. Pediatrics 79: , Kuppermann N, Bank DE, Walton EA, et al: Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis. Arch Pediatr Adolesc Med 151: , 1997.

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