URINARY TRACT INFECTIONS IN CHILDREN

0031-3955/97 $0.00

PEDIATRIC UROLOGY

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URINARY TRACT INFECTIONS IN CHILDREN EPIDEMIOLOGY, EVALUATION, AND MANAGEMENT H. Gil Rushton, MD, FAAP

Over the past decade we have gained many new insights into the etiology and pathophysiology of urinary tract infections (UTIs) in children. The role of bacterial virulence in the etiology of UTIs has been emphasized by our infectious diseases colleagues. Several genetically coded bacterial virulence factors have been identified that enhance the potential of uropathogenic organisms to cause symptomatic disease, such as the ability of certain strains of bacteria to adhere or attach to human uroepithelium. Interacting with these virulence factors are a multitude of host defense factors operating at every level of the urinary tract, ranging from the perineum to the renal parenchyma. These complex host-parasite interactions determine an individual’s susceptibility to urinary infection. Experimental studies combined with clinical observations have clearly demonstrated the critical role that infection plays in producing irreversible renal scarring, the most severe long-term sequelae of childhood UTIs. This awareness has led to greater emphasis being placed on the nonsurgical management of conditions, such as vesicoureteral reflux ( W R ) and nonobstructive hydronephrosis. Meanwhile, the recognition of the important role of voiding and bowel dysfunction in the cause of recurrent UTIs has led to improved management of these children,

From the Department of Pediatric Urology, Children’s National Medical Center; and the Departments of Urology and Pediatrics, The George Washington University School of Medicine, Washington, DC

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 44 NUMBER 5 * OCTOBER 1997

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who were previously subjected to unnecessary and usually ineffective cystoscopic procedures and urethral dilations. The imaging modalities involved in the evaluation of children with UTIs have also changed with replacement of intravenous pyelography (IVP) by sonography, renal cortical scintigraphy, or both. Sonography is a noninvasive, painless technique that has been shown to be as sensitive as IVP for the detection of significant structural abnormalities of the urinary tract. The use of technetium Tc 99m (%"'Tc)-labeled dimercaptosuccinic acid (DMSA) renal scans has allowed for accurate identification of acute pyelonephritis and the ability to document the extent and progression of renal parenchymal damage. This has led to further refinement of therapeutic regimens, such as outpatient management of children with acute pyelonephritis. The use of renal cortical scintigraphy has confirmed a higher than previously recognized incidence of nonreflux pyelonephritis in children. As documented by DMSA scans, acute pyelonephritic damage can be reversed in many cases with prompt diagnosis and antibiotic therapy. In others, severe scarring results despite appropriate therapy. Case History A 9-month-old girl was admitted for her first known febrile UTI. Her temperature was elevated to 104°F for 2 days associated with poor appetite and lethargy. Urinalysis on a catheterized specimen revealed pyuria and bacteriuria. After urine culture was obtained, she was started on intravenous antibiotic therapy with gentamicin and ampicillin. Renal and bladder sonography revealed mild-moderate dilatation of the right renal pelvis (Fig. 1). The right kidney measured 7.2 cm in length, and the left kidney measured 6.9 cm in length. A DMSA renal scan obtained at that time demonstrated almost complete nonfunctioning of the right kidney (Fig. 1). Approximately 1 month later, a repeat sonogram revealed that the right kidney now measured only 4.9 cm in length. A repeat renal scan demonstrated some recovery of renal function, but the child was now left with a small, scarred right kidney that contributed only 17% of total renal function.

This case vividly illustrates the potential for severe renal parenchymal damage, which can follow a single severe UTI in young children. It is this potential for significant morbidity from UTIs in childhood that has led to the current emphasis on early and accurate diagnosis, prompt antibiotic treatment, and early evaluation of the urinary tract of infants and young children with documented infections. EPIDEMIOLOGY

UTIs in children may be symptomatic or asymptomatic. Those that are symptomatic may be confined to the bladder (i.e./ cystitis), or they may involve the upper collecting system (i.e., ureteritis or pyelitis), or extend into the renal parenchyma (i.e., pyelonephritis) (Fig. 2). The

Figure 1. A 9-month-old girl was hospitalized with her first febrile urinary tract infection. A, Initial sonogram (12/2/86) shows moderate hydronephrosis of right kidney. Renal length measures 7.2 cm compared with 6.9 cm on the left. Voiding cystogram demonstrates right grade I V N vesicoureteral reflux. Follow-up sonogram 5 weeks (1/6/87) later reveals generalized scarring and contraction of the right kidney, which now only measures 4.9 cm in length. B, Initial DMSA renal scan at time of acute urinary tract infection demonstrates marked diffuse decrease in uptake by right kidney consistent with generalized acute pyelonephritis. Three weeks later, a DTPA renal scan shows a small right kidney which contributes only 17% of total renal function. (From Rushton HG: Genitourinary infections: Nonspecific infections. In Kelalis PP, King LR, Belman AB (eds): Clinical Pediatric Urology, ed 3. Philadelphia, WB Saunders, 1992.)

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Cystitis

Ureteritis/Pyelitis

Pyelonephritis

Figure 2. Sites of acute urinary infection. (From Rushton HG: Genitourinary infections: Nonspecific infections. In Kelais PP, King LR, Belman A 6 (eds): Clinical Pediatric Urology, ed 3. Philadelphia, WB Saunders, 1992.)

prevalence of symptomatic and asymptomatic bacteriuria (ABU) in childhood is influenced by the age and sex of the patient as well as the method of diagnosis. The overall incidence of neonatal bacteriuria has been reported as 1.0% to 1.4%.', 74,93 The male-to-female ratio in neonates is reversed from that seen in older children, with boys outnumbering girls 2.8:l to 5.4:1.7,'* The actual incidence of UTIs during infancy has probably been underestimated in the past, partly because of the nonspecificity of symptoms and the inability of this age group to verbalize. In a 3-year prospective screening study of 3581 infants (newborns to 1 year of age) in Goteborg, Sweden, screening bacteriuria confirmed by suprapubic aspiration of urine was found in 2.5% of boys and 0.9% of girls.5I Symptomatic bacteriuria occurred almost equally in both sexes (1.2% of boys and 1.1% of girls). Overall, 3.7% of boys and 2.0% of girls had bacteriuria during the first year of life. The male dominance in the incidence of UTIs during the first few months of life also has been reported in the United States.26* 8o During preschool and school age, the sex ratio for screening bacteriuria is reversed from that seen in infancy, ranging from 0.7% to 1.9% of girls to 0.04% to 0.02% of boyss, 71, 92, '16, '17; however, the term screening bucteriuria is misleading in that as many as one third of these children had a prior history of UTI, and many also had a history of voiding symptoms. In their classic prospective epidemiologic study of symptomatic UTIs in children living in Goteborg, Sweden, Winberg and colleagues14oestimated that the aggregate risk for symptomatic UTI up to age 11 years was at least 3.0% for girls and 1.1% for boys. In a more recently updated report from the same the actual prevalence of culture-documented symptomatic UTIs in children up to age 7 years was almost twice as high as previously estimated, affecting 7.8% of girls and 1.6% of boys. Approximately half of the girls and two thirds of the boys experienced high fever with these infections. In fact, UTIs have recently been described as one of the most common serious bacterial illnesses among febrile infants and young children, with a reported

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prevalence ranging from 4.1% to 7.5%.43These figures suggest that the true frequency of UTIs in children has been underestimated in the past. BACTERIOLOGY

Most uncomplicated UTIs are caused by a large family of gramnegative, aerobic bacilli known as Enterobacteriaceae. Included in this family are the Escherichia, Klebsiella, Enterobacter, Citrobacter, Proteus, Providencia, Morganella, Serratia, and Salmonella species. Of these, Escherichia coli is by far the most frequently isolated organism, being responsible for approximately 80% of UTIs. Identification of all of these organisms by standard culture techniques is routine and available in all laboratories and many office practices. Pseudoomonas sp is also a gram-negative, aerobic bacillus but is distinct and unrelated to Enterobactericeae. Most of the Pseudomonas organisms recovered from the urine are of relatively low virulence and do not tend to invade tissue unless the host defense mechanisms are compromised. The most common gram-positive organisms found in UTIs are Staphylococcus and Enterococcus sp. Anaerobic fecal flora rarely produce UTIs despite being 100 to 1000 times more Io3 abundant than E. coli in Virulence Factors

The term virulence simply refers to the ability of microorganisms to cause disease. The concept of uropathogenic bacteria refers to certain strains that are selected from the fecal flora, not by chance or based on prevalence, but because of the presence of specific virulence factors that enhance colonization of the uroepithelium. Other virulence factors aid in persistence of bacteria in the urinary tract and provide these organisms with the capacity to induce inflammation of the urethra, bladder, or renal parenchyma. Specific recognized E. coli virulence factors include, but are not limited to, adherence to uroepithelial cells, high quantity of K antigen in the capsule of the bacteria, hemolysin production, colicin production, the ability of bacteria to acquire iron, and resistance to serum bactericidal activity. Adherence

Bacterial adherence or attachment is an essential initiating step in all infections. Tissue invasion, inflammation, and cell damage are secondary events. Uropathogenic bacteria can attach to specific receptor sites on the uroepithelium and also can bind in a nonspecific manner by electrostatic and hydrophobic factors. By virtue of such attachment, virulent strains of bacteria can ascend into the upper urinary tract even in the absence of structural abnormalities, such as VUR. Specific attachment to

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uroepithelial cells is mediated by adhesins localized either in an outer coat or capsule or on specialized pili (also known asfirnbriae) (Fig. 3). Several different fimbriae or pili have been identified. Clinical and experimental studies have shown that pyelonephritic E. coli frequently possess fimbriae that can recognize and agglutinate erythrocytes of the P1 blood group; hence this type of pili has been labeled P-fimbriae. The P-fimbriae recognize and attach to a specific carbohydrate receptor contained within the P blood group antigen, which also is present on human uroepithelial cells.57,70 In addition to its role in colonization of the urinary tract, adherence mediated by P-fimbriae also may provide more efficient delivery of endotoxin, present in the capsule of all E. coli, to the uroepithelial tissue.*l Endotoxin is an important mediator of the local and systemic inflammatory responses to infection. Epidemiologic studies in adults and children have provided considerable evidence that the presence of P-fimbriae on E . coli is a significant virulence factor, particularly in upper UTIs. These studies have shown that 76% to 94%of pyelonephritogenic strains of E. coli are P-fimbriated, compared with 19% to 23% of cystitis strains, 14% to 18% of strains

‘ OUTER MEM0RANE

f IipOpolysocchoride, /@oproteinl

SOL ID M€MB?AN€

INNER CYTOPLASMIC M€M%RANE

CAPSULE .’ “/(“antigenof E , coli Figure 3. Antigenic structure of gram-negative bacteria. (Adapted from Young LS,Martin WJ, Meyer RD, et at: Gram-negative rod bacterernia: Microbiologic, immunologic, and therapeutic considerations. Ann Intern Med 86:4546, 1977; with permission.)

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isolated from patients with ABU, and 7% to 16% of fecal isolate 131 Other evidence supporting the importance of P-fimbriae in causing upper UTIs comes from animal model studies. Inoculation of the bladders of nonrefluxing primates with P-fimbriated E. coli resulted in pyelonephritis in 66% of animals. In contrast, pyelonephritis was not seen in any of the monkeys inoculated with non-P-fimbriated E. c0L109 Despite its significance, bacterial adherence is only one of several factors believed to have a role in infection. Other bacterial virulence factors and host defense factors may play an even greater role in tissue invasion and inflammation. In an experimental study in mice, the presence of P-fimbriae was necessary for colonization of the upper urinary tract but did not produce tissue invasion unless combined with other virulence factors.94Similarly, in a clinical study of children with febrile UTI, no difference was shown in the incidence of P-fimbriated E. coli in those who had acute inflammatory parenchymal damage documented by DMSA renal scans versus those whose scans were normal, suggesting a role for other virulence factors in producing tissue invasion and damage.80Likewise, postpyelonephritic renal scarring has been reported to be more common following infections caused by non-E. coli organisms compared with those caused by P-fimbriated E. C O Z ~ . These ~~ studies underscore the complexity of the host-parasite interaction in the cause of UTIs and renal scarring and suggest that the characteristics of bacterial virulence for acute UTI may differ from those for renal scarring. Other Virulence Factors

K antigen, a capsular polysaccharide, has been shown to shield bacteria from complement lysis and phagocytosis and to enhance persistence of bacteria in the kidneys of experimental mice.@,129 It is more commonly isolated in children with clinical pyelonephritis than in children with cystitis or healthy controls.55Hemolysins, another recognized virulence property, are cytotoxic proteins that are capable of damaging renal tubular cells in vitro. Hemolytic strains of E. coli produce more severe experimental pyelonephritis in mice.133Colicin, another protein elaborated by pyelonephritogenic E. coli, kills other bacteria in the vicinity of the E. coli producing it. The colicin V plasmid is also thought to encode for an iron uptake system, which further promotes the survival l ~ ~ bacteria reand pathogenicity of colicin-producing 0 r g a n i ~ m s . Most quire iron for optimal growth and metabolism and have developed mechanisms to acquire iron when there is limited supply. Iron-binding capacity, mediated by proteins such as aerobactin, has also been shown to be associated with increased virulence in epidemiologic studies.l3,45 Finally, in the presence of fresh human serum, many strains of E. coli are killed following activation of complement. Serum resistance to such killing action is another property that has been related to virulence of gram-negative bacteria in UTIs and gram-negative bacteremia.84,95 Although these virulence factors have been considered separately,

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the effect of virulence properties seems to be additive. Most isolates in patients with nonreflux acute pyelonephritis express three or four virulence properties in contrast to those with cystitis or ABU.77Interestingly, the frequency of P-fimbriae and other virulence factors is significantly lower in patients who have VUR. This seems logical because, in the presence of reflux, virulence properties such as adherence are not necessary for bacteria to reach the upper urinary tract. Host Defense Factors Interacting with bacterial virulence properties are an equally important and complex number of mechanical, hydrodynamic, antiadherent, receptor-dependent and immunologic host factors that affect an individual’s susceptibility to UTIs. By necessity, these factors are closely interrelated to the pathogenesis of UTIs, beginning with the route of entry of bacteria into the urinary tract. Perineal and Urethral Factors Considerable clinical and experimental evidence has clearly established an ascending or retrograde urethral route of entry of bacteria in most UTIs. The usual organisms originate from fecal flora that colonize the perineum.32The same bacterial strains causing urinary infections in women and children with recurrent infections can be found on perineal cultures before bladder invasion.lO,68, lZ5This is in contrast to negative perineal cultures in healthy controls. It has been proposed that the possible exception to this concept may be newborn infants, in whom a hematogenous route has been suggested. This proposal is based on the more frequent finding of bacteremia associated with UTI in this age group26;however, others have not substantiated a higher incidence of bacteremia in neonates compared with older infants and children with febrile LJTIs.8O Furthermore, the increased risk for UTIs (including pyelonephritis) in uncircumcised boys compared with both girls and circumcised boys provides additional convincing support for an ascending route of infection even during the first several months of life. In fact, more than 90% of boys with febrile UTIs during the first year of life are uncircumcised.26,113 Wiswell and colleague^'^^^ 143 documented a 10- to 20-fold increase in the incidence of UTIs in uncircumcised male infants compared with female infants and circumcised male infants. This risk corresponding to the time appears to extend up until 1 year of period when heavier colonization of the prepuce by gram-negative bacteria has been noted by others.l0Zl1 In vitro studies reveal that pathogenic fimbriated E. coli adhere well to the mucosal surface of the prepuce, whereas nonpathogenic E. coli do not.24Thus, colonization of the prepuce by uropathogenic bacteria in infant boys suggests an ascending route of infection similar to that described in older girls. Consequently, circumci-

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sion may help to prevent UTIs in male infants by removal of the mucosal surface necessary for bacterial adherence to occur. The short urethra in girls seems to be the most obvious explanation for the increased relative incidence of UTIs in girls compared with boys past the first 6 to 12 months of life. Narrowed urethral caliber, historically blamed as the pre-eminent factor influencing susceptibility to lower UTIs in girls, does not play a role. It has long been established that the intrinsic urethral luminal size is not significantly smaller in girls who are bacteriuric compared with those who have never been infected.30,52 Consequently, urethral dilation or other cystoscopic procedures have no role in the routine management of childhood UTIs. Other commonly held misconceptions related to the causes of UTIs are that improper wiping techniques and bubble baths predispose to UTIs. No evidence is available to support these myths. The strongest evidence against improper wiping techiques being a cause of UTIs is that more than 95% of non-toilet-trained infants never develop UTIs despite daily exposure to soiled diapers. Although bubble baths may occasionally cause dysuria from local meatal or vaginal irritation, there is no association with bacterial cystitis. More important for urethral ascent into the bladder is the ability of uropathogenic bacteria to attach to uroepithelial cells. Similar to the findings with periurethral increased adherence of bacteria to uroepithelial cells has been demonstrated in children prone to UTIS,'~Oimplying a difference in host receptor density or affinity that influences an individual's susceptibility to infection.

Bladder Factors The elimination of bacteria from the bladder by frequent and complete bladder emptying plays a significant role in preventing infe~tion.'~ Various types of voiding dysfunction have been described in children. These types range from a small-capacity, unstable bladder characterized by frequency, urgency, daytime enuresis, and posturing to infrequent voiding with a large capacity bladder that empties poorly. Constipation, encopresis, or both often accompany infrequent voiding. Numerous reports have linked dysfunctional voiding and recurrent UTIS.~,33, 34, 39, 63, 132 Attention also has been focused on the association between dysfunctional voiding and the presence of VUR in children with recurrent U T I S . ~The ~ , ~predisposition ~ to recurrent UTIs and W R in children with dysfunctional voiding is related to the presence of residual volume resulting from inadequate emptying of the bladder, increased intravesical pressure created by uninhibited bladder contractions, and bladder overdistension from infrequent voiding habits. The establishment of normal voiding habits in these children has been shown to reduce the incidence of recurrent UTIs. Similarly, there is a definite correlation between constipation and recurrent UTIs in children.91,96 Although this theoretically may be the result of mechanical factors related to compression of the bladder and

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bladder neck by a hard mass of stool, it is more likely caused by the frequent coexistence of constipation with dysfunctional voiding and incomplete bladder emptying. Improvement in bowel habits generally results in a decrease in the incidence of recurrent UTIs in some patients, particularly when coupled with a more normal voiding pattern. UPPER URINARY TRACT Numerous reports have documented that VUR is present in 25% to 50% (average, 35%) of children with culture-documented UTIs.lZ0In contrast, in a survey of the literature, Bailey5 reported an incidence of VUR in children without UTIs of only 0.4% to 1.8%. Similar findings were reported by Ransley,'O' who compiled voiding cystograms in 535 children without a history of UTI and found W R in only 7 (1.3%). W R , when present, continues to be the most significant single host risk factor in the etiology of childhood pyelonephritis. The risk for acute pyelonephritis and subsequent renal scarring is related to the severity of VUR. In one prospective study of children with febrile UTIs, approximately 80% of patients with VUR demonstrated acute pyelonephritic changes of the renal parenchyma on 99mTc-DMSA renal scans, including 100% of patients with moderate or severe reflux (grades III-V/V)."O In contrast, only 60% of patients without demonstrable reflux had evidence of acute pyelonephritis on the DMSA scans. Kidneys with moderate or severe reflux were twice as likely to demonstrate abnormalities on DMSA scans (67%)compared with kidneys with mild (32%) or no reflux (34%). In a compilation of 10 published clinical studies of children with febrile UTIs, DMSA renal scan abnormalities were reported in 50% to 80% of children.'12 When VUR was present, approximately 80% to 90% of patients had abnormal studies, including almost all with moderate or severe VUR. The presence of VUR seems to compensate for virulence of E. coli in patients with recurrent pyelonephritis.n When there is reflux of infected urine from the bladder into the upper urinary tract, bacteria do not require special virulence properties, such as attaching ability, to ascend from the bladder to the kidney. In one study of girls with recurrent pyelonephritis, infections were caused by P-fimbriated E. coli in only 36% of those with VUR compared with 71% of those without VUR.77Despite the important role that VUR plays when it is present, several studies of children with febrile UTIs have reported that most patients (6O-68%) with abnormal DMSA renal scans demonstrating acute pyelonephritic changes do not have demonstrable VUR at the time of investigation.'I2 In children without reflux, the P1 blood group phenotype may contribute to the susceptibility to recurrent pyelonephritis, possibly because of a higher content of specific receptors for attaching E. coli on uroepithelial cells.75All of this underscores the importance of other host defense factors and bacterial virulence in the pathogenesis of acute pyelonephritis in children.

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Obstruction and other severe malformations of the upper urinary tract often present clinically as infection and are obvious predisposing factors to renal damage. Obstruction may occur at the ureteropelvic junction, the ureterovesical junction, or the posterior urethra in boys with valves. Other important malformations associated with obstruction include ectopic ureters, with or without associated ureteroceles; however, such anomalies are in fact found in only a small minority of children with UTIs. The increased predisposition to infection results from impairment of urinary flow with resultant stasis that compromises bladder and renal defense mechanisms. Both obstruction and high-grade W R result in an increase in the residual volume of urine in the bladder or dilated urinary tract, permitting the multiplication of bacteria in the urine.I7These conditions also inhibit the mechanical washout or flushing effect of effective micturition or ureteral peristalsis and may alter other local defense factors. All of these processes result in increased susceptibility of the parenchyma to infection and damage. CLINICAL PRESENTATION

The classic signs and symptoms for UTIs often do not present themselves in very young people. Instead, nonspecific symptoms, such as irritability, poor feeding, failure to gain weight, vomiting, and diarrhea, may be the only signs suggestive of an underlying problem. Often absent in neonates, fever is present in most infants (1-12 months of age) with symptomatic UTIS.'~OBecause this may be the only specific symptom, a urine specimen for culture should be obtained whenever a nonverbal, non-toilet-trained child presents with unexplained or very high fever. As the child becomes verbal and toilet-trained, UTI symptoms are more easily detected. Fever continues to be relatively common in toddlers with first-time symptomatic infections; however, fever is not as frequently associated with recurrent or long-standing infection. In older children, urgency, frequency, enuresis, and dysuria are common presenting symptoms. It is clear, however, that these lower tract symptoms do not always represent bacterial infection and may be the result of vulvitis, urethritis, or dysfunctional voiding. For example, the daytime urinary urgency-frequency syndrome of childhood is characterized by extremely frequent, rushed daytime voiding of small amounts of urine. These children rarely actually wet and can usually sleep throughout the night without enuresis or significant nocturia, although they often get out of bed to urinate several times before actually falling asleep. This syndrome is not associated with infection, pyuria, or increased incidence of underlying uropathology.62It is a self-limiting condition and is presumed to be anxiety or stress related. Consequently, antibiotics and anticholinergics are usually not beneficial. In a prospective population-based epidemiologic study of UTIs in children from Goteborg, Sweden, Jodalsl reported on 952 girls and 225

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boys less than 10 years of age who were diagnosed with a first-time UTI. Of the 225 boys, 59% presented during the first year of life. The number of boys diagnosed in the higher age groups was low, especially beyond 5 years of age (Fig. 4). In girls the frequency of first UTIs was highest in the first year of life and, like boys, more than 90% of these infections were consistent clinically with pyelonephritis. In girls a second peak incidence was noted between the ages of 2 and 5 years, ages that coincide with toilet training and that may be associated with the onset of dysfunctional voiding. A much higher percentage of the infections in this older group were consistent clinically with cystitis (Fig. 4).

Cystitis

Acute cystitis in children rarely is associated with significant longterm morbidity. Typical symptoms that accompany acute cystitis in toilet-trained children include dysuria, frequency, urgency, and secondary onset enuresis. As previously mentioned, these same irritative lower tract symptoms are often seen in the absence of bacterial cystitis, mandating that a specimen for urine culture be obtained before institution of therapy. Fever and systemic complaints are generally not a feature of the clinical picture. The recurrence rate of lower UTIs is quite high.65*140 Many children who have recurrences are recognized as being dysfunctional voiders (see section on Bladder Factors).

Asymptomatic Bacteriuria

The natural history and uroradiographic findings in patients with ABU or covert bacteriuria vary according to the age of the patient and prior episodes of symptomatic infections. A study of ABU and symptomatic bacteriuria in infants less than 1 year of age reveals interesting differences in the two population~.~* Among those patients with symptomatic infections, 14 of 39 (36%) had reflux, including three with grade I11 or higher. In patients with ABU, only mild reflux was found, occurring in 5 of 46 patients (11Y0).Clinical pyelonephritis developed in only 2 of 50 patients with ABU, occurring within 2 weeks of detection. Of 45 left untreated, 37 spontaneously cleared the bacteriuria, and seven others became abacteriuric following antibiotic treatment for other reasons. Although asymptomatic recurrences developed in six patients (13%), no pyelonephritic recurrences occurred in this group during follow-up of at least 1 year. Follow-up urography, performed in 36 patients, did not reveal any evidence of renal scarring. In contrast, in the intially symptomatic group, 14 of 40 patients (35%) experienced recurrences, including six with acute pyelonephritis and three with cystitis. It was concluded that infants with ABU represent a low-risk

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180

BOYS n=225 160

0

140

a

a

120

2

E, t

UTI, unspecified

Cystitis Pyelonephritis

loo

80 60

40

20 0

A

Age, Years

in

I - I '

B

GIRLS 111952

u

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u r n

Pyelonephritis

Age, Years

Figure 4. A and B, Children with first-time diagnosis of urinary tract infection at the Children's Hospital in Goteborg, Sweden, from 1970 to 1979 according to age and clinical diagnosis. (FromJodal U: ln Holliday M, Barratt TM, Avner ED (eds): Pediatric Nephrology, ed 3. Baltimore, Williams & Wilkins, 1994; with permission.)

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group with a tendency to spontaneously become abacteriuric, usually within a few months. In school-aged children, considerable variation in uroradiographic findings has been reported in those found with bacteriuria on screening. These studies have reported VUR in 19% to 35% and renal scarring in 10% to Z6%66, 85, 92, lI6; however, many of these children had a prior history of symptomatic UTIs and others undoubtedly had infections during infancy that were overlooked or misdiagnosed. The risk for acute pyelonephritis in girls older than 4 years of age with untreated ABU is small and seems to be associated with a change in bacterial strain, often as a result of antibiotic Follow-up by the Cardiff-Oxford Bacteriuria Study Group revealed that schoolchildren who presented initially with a radiographically normal urinary tract remained normal despite persistent ABU.14Only children who had previous renal scarring developed new scars, and all of these children had W R . Other studies have shown that ABU is associated with low-virulence bacterial strains lacking the ability to adhere and cause ~ y m p t o m s . ~There * ~ ~ ~is*considerable clinical and experimental evidence that these organisms may be commensal with the host and may even protect against infection by more virulent strains” Based on this information, it is reasonable that true ABU, particularly in older girls, be left untreated.73,lZ8 717

Pyelonephritis

Acute pyelonephritis represents the most severe type of UTI in children. It not only results in greater acute morbidity but also has the greatest potential for causing irreversible damage. Older children with acute pyelonephritis typically present with fever and flank pain or tenderness associated with pyuria and positive urine culture. In most cases, laboratory evaluation reveals an elevated serum white blood count, erythrocyte sedimentation rate, and/or C-reactive protein; however, when compared directly with localization studies, such as DMSA renal scans, these clinical and laboratory parameters are associated with high false-positive and false-negative rates.l12This is particularly true in neonates and young infants, an age group at greatest risk for renal scarring following pyelonephritis. When one considers that approximately half of all children with febrile UTIs present during the first year of life, the importance of early and accurate diagnosis becomes obvious. A brief review of the pathogenesis of pyelonephritis and renal scarring is fundamental to the rationale for evaluation and management of children with UTIs. Experimental studies by Roberts and others clearly suggest that the same acute inflammatory response that is responsible for the eradication of bacteria is also responsible for the damage to renal tissue and subsequent renal scarring.105Through a series of experimental studies using the primate model, Roberts developed a unified theory of the chain of events involved in the process that ultimately leads to renal scarring (Fig. 5). The iniating event is bacterial

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PATHOGENESIS OF ACUTE PYELONEPHRITIS CHAIN OF EVENTS Bacterial inoculation of renal parenchyma

J

Immune response

Complement activation

-

Chemotaxis Opsonization

J, Phagocytosis Bacterial killing

....................

Superoxide release

Iysozyme Tubular cell death

JI Interstitial invasion

lntravascular granulocyte aggregation

I Focal ischemia

RENAL SCAR Figure 5. Hypothesisfor the pathogenetic chain of events in acute pyelonephritis. (Adapted from Roberts JA: Pathogenesis of pyelonephritis. J Ural 129:1102, 1983; with permission.)

inoculation of the renal parenchyma, which elicits immune and inflammatory responses. Although the immune response can be elicited by either live or heat-killed bacteria, the acute inflammatory response occurs only following inoculation by live bacteria.Io7Because heat-killed bacteria do not cause renal scarring, it seems that it is the acute inflammatory response that is more important in the subsequent development of permanent renal damage. Inflammation releases toxic enzymes, such as lysozymes, within the granulocyte and into the lumen of the renal tubules. At the same time, superoxide is released, which generates oxygen radicals that are toxic not only to the bacteria but also to the surrounding tubular cells.1o8Tubular cell death results, spreading the inflammatory process into the interstitium, causing even further damage. At the same time, focal ischemia results from intravascular aggregation of granulocytes and edema.54The interstitial damage produced by the combined effects of toxic enzymes, oxygen radicals, and ischemia ultimately leads to renal scarring.lo6

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Recent clinical evidence from studies of children with acute pyelonephritis documented by DMSA renal scans strongly supports the conclusions drawn by Roberts and colleagues. Several investigators have evaluated the evolution of the acute inflammatory changes associated with pyelonephritis using serial DMSA renal scans. Acute pyelonephritic damage has persisted as permanent scarring in 36% to 52% of kidneys.46, 111, 115, 134 The sites of new renal scarring have corresponded to those sites of acute pyelonephritis seen on the initial DMSA renal scans, confirming the primary role of the acute inflammatory response to infection in the cause of renal scarring (Fig. 6). These serial changes have been observed in the presence and absence of VUR/6, lT5 providing convincing clinical evidence that renal parenchymal infection, rather than VUR, is the prerequisite for acquired renal scarring. However, as noted earlier, kidneys with associated VUR, particularly moderate and severe grades, are at higher risk for acute pyelonephritis in the first place. Furthermore, the correlation between the severity of VUR and renal scarring is well

Figure 6. DMSA renal scan in a 13-month-old girl who presented with an acute febrile urinary tract infection. A, Left posterior oblique view on initial DMSA scan demonstrates acute pyelonephritis involving the midzone of the left kidney with typical findings of a focal decrease in uptake of DMSA with presetvation of the normal renal contour. B, Follow-up DMSA scan reveals progression to renal scar characterized by contraction and loss of functioning renal cortex. (From Rushton HG, Majd M, Jantausch B, et al: Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99mtechnetiumdimercaptosuccinic acid scintigraphy. J Urol 147:1327, 1992; with permission.)

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1149

Table 1 . RENAL SCARRING COMPARED WITH GRADE OF REFLUP Grade of Reflux

Percent with Scarring?

1 2

6

3 4 5

5 17 25 50

'Total number of kidneys evaluated = 804. tTotal number of kidneys with scarring = 97 (12%). Modified from Skoog SJ, Belman AB, Majd M: A nonsurgical approach to the management of primary vesicoureteral reflux. J Urol 138:441, 1987.

established (Table 1).8,51, 119 Thus, VUR remains one of the most significant host risk factors for renal scarring. Regarding the role of infection in the cause of renal scarring, new or progressive scarring is almost always associated with a history of UTI.lZ3Furthermore, a clear association exists between the number of pyelonephritic attacks and incidence of renal s~arring.~' Experimental and clinical studies also have shown that some renal scarring can be prevented or diminished by early antibiotic treatment of acute pyelonephritis (Fig. 7).27,46, lo2,lo4,115 Furthermore, when VUR is present, new renal scarring can be prevented successfully by keeping the patient free of infection.

DIAGNOSIS Urinalysis UTIs can be reliably diagnosed only by culture. Symptoms of dysuria, urgency, frequency, and enuresis are nonspecific and may be the result of vulvitis; urethritis; dysfunctional voiding; or nonspecific causes, such as dehydration associated with a febrile illness. Although routine urinalysis can be helpful in calling attention to those who might be infected, the association of inflammatory cells in the urine by itself is at best only approximately 70% reliable.l5.26, loo The finding of significant pyuria on routine urinalysis varies with the volume of urine centrifuged and examined, the force and duration of centrifugation, the volume in which cells are resuspended, and observer error.'" Urine microscopy for bacteria significantly improves the reliability of urinalysis for the detection of urinary infection, particularly when one combines this with examination of the urinary sediment for pyuria."O More recently, Hoberman and colleague^^^ reported that an "enhanced" microscopic analysis of uncentrifuged urine, which included a leukocyte count measured by a hemocytometer and a Gram-stained smear interpreted by an experienced laboratory technician, provides a high sensitivity and positive

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predictive value for the identification of positive urine cultures. In a subsequent study by the same authors, the finding of pyuria alone in 4253 febrile children would have detected approximately 89% of 212 patients with positive urine cultures. Enzymatic Tests

Partly as a result of the technique and operator-dependent variability with urine microscopy, several enzymatic methods for detection of pyuria or bacteriuria have been developed. The leukocyte esterase dipstick test demonstrates the presence of pyuria by histochemical methods that specifically detect esterases in the neutrophils. When compared with chamber count methods, studies have reported sensitivity as high as 88% to 95% for the detection of pyuria using a cutoff of 10 or more in a recent study that evaluated 110 l e ~ k o c y t e s / m m ~67. ~However, ~, children with fever and positive urine cultures, the leukocyte esterase test had sensitivities of only 52.9% and 66.7% in detecting more than 10 and more than 20 leukocytes/mm3, respecti~ely.~~ Furthermore, one would not anticipate this test to be any more sensitive than the finding of pyuria alone for the identification of children with positive urine cultures. Bacteria convert nitrate normally present in the urine to nitrite. The nitrite method uses reagent paper impregnated with sulfanilic acid and alpha-naphthylamine, which forms a red azo dye when in contact with nitrite. Thus, a positive colorimetric reaction implies the presence of bacteria in the bladder; however, a relatively long incubation period (4 h) is required for conversion of nitrate to nitrite. For this reason, the first morning urine sample in a toilet-trained child is the best specimen to test. A single test on randomly collected urine specimens was reported to have a sensitivity of only 29.2% to 44.9% on 790 urine specimens using dipsticks from two manufacturers; however, the specificity was 98% when the test was positive.47This test is not a reliable office screening method when used alone.82 Combining the leukocyte test and the nitrate test on a single dipstick has improved the ability to detect or exclude UTIs. In a review of rapid methods to detect UTIs, Pezz10~~ reported a sensitivity of 78% to 92% and a specificity of 60% to 98% when using the combination test. Based on this information, it may be reasonable to eliminate the urine culture when the dipstick test is negative and the index of suspicion based on clinical symptoms is low; however, specimens for urine culture should be obtained in all patients with either positive dipstick test findings or when the clinical index of suspicion is high. Urine Culture

In pre-toilet-trained children, the urine specimen for culture is often initially obtained by applying a collection bag (U-Bag) to the perineum.

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Although this method has been justifiably criticized for producing a high rate of contamination, the technique is reliable when the culture is negative. Contamination is directly related to the length of time the collection device remains applied to the child. If a specimen has not been obtained within 30 minutes of application, reliability begins to decrease. Removing the appliance and plating or refrigerating the urine immediately after the child voids is paramount. Having the parent apply the bag before leaving for the physician’s office in an effort to shorten the wait is acceptable only when the specimen for culture is negative. Confirmation of all positive urine specimens for culture is advisable before treatment. Consequently, catheterization or suprapubic aspiration (SPA) should be used when the clinical situation dictates immediate treatment. A feeding tube (8 to 10 French catheter) inserted only a few centimeters into the bladder is ideal for catheterization. SPA has achieved popularity in some centers. Young children are particularly favorable candidates for SPA because of the abdominal location of their urinary bladders; however, the procedure cannot be expected to be successful when the bladder is empty. This is the major drawback of SPA. If urine is not obtained initially, time should not be wasted in sick children who require antibiotic treatment. Urethral catheterization should be performed. SPA is performed after first cleaning the suprapubic area with an antiseptic solution. A 21- to 25-gauge needle is inserted perpendicular to the patient in the midline one fingerbreadth above the symphysis. Although a local anesthetic can first be infiltrated, it seems unnecesary and may actually cause more pain than a quick in-and-out aspiration. It is practical to apply a U-Bag to the perineum prior to cleansing the abdomen. Many children void during preparation for aspiration, obviating the necessity for that procedure if the voided urine is immediately plated or refrigerated. It has often been stated that ”any number of bacteria” obtained by suprapubic bladder puncture are significant. Because the bladder is a reservoir, and this method of collection depicts the number of bacteria in that reservoir, one should not anticipate colony counts significantly different from those properly collected by other means. Ginsburg and McCrackenZ6found more than 100,000 colony forming units (CFU)/mL in 96% and 40,000 to 80,000 in the remaining 4% of 100 infants with bacilluria demonstrated on SPA. None showed fewer than 40,000 colonies. Nelson and Peters90 had previously reported similar results in a study of premature and term infants. Hoberman and c o l l e a g ~ e sre~~ cently reported the results of positive urine cultures on specimens obtained by catheterization in 110 febrile infants less than 2 years old. Of 110 urine cultures with more than 10,000 CFU/mL, 92 (84%) had more than 100,000 CFU/mL, 10 (9%) had 50,000 to 99,000 CFU/mL, and only 8 (7%) had 10,000 to 49,000 CFU/mL. Furthermore, urine specimens with 1000 to 49,000 were more likely to yield gram-positive or mixed organisms than specimens with more than 50,000 CFU/mL. These authors concluded that UTI is best defined by more than 10 leukocytes/ mm3 and colony counts of more than 50,000 on catheterized specimens.

URINARY TRACT INFECTIONS IN CHILDREN

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Thus, colony counts from the bladder of less than 10,000 CFU/mL are suspect regardless of the manner in which that urine was collected.

EVALUATION

Rationale for Early Evaluation

Recommendations for evaluation UTIs in children vary. The current trend toward early evaluation of young children following their first documented UTI is based on epidemiologic and clinical data. Experimental studies and clinical observations in children have proven that significant renal scarring can occur after a single UTI (see case history; Io2, Iz3 A higher incidence of renal scarring has been reported Fig. l).46, in children with VUR and recurrent UTIs compared with those with W R who have had only a single infection.121,’41 Similarly, Joda150 reported a strong association between the number of pyelonephritic episodes and the incidence of renal scarring (Fig. 8). Recurrence of UTI within 1 year of a preceding infection occurs in approximately 30% of girls with one, 60% with two, and 75% with three prior infection^.'^" Data collected by K ~ m i nin~school-aged ~ girls revealed that recurrence of infection occurred in 80% of white girls and in 60% of black girls within 18 months. Furthermore, because signs and symptoms that typically accompany UTIs in infants and toddlers are frequently nonspecific, it is often impossible to determine whether an infection actually represents the first episode.140 The yield from the evaluation of children with culture-documented UTIs is high. Radiographic studies of white girls with symptomatic UTIs reveal the presence of VUR in approximately 35% to 50% of cases.51,lZo Unfortunately, clinical parameters have proven unreliable in distinguishing children with UTIs who also have VUR.lZ1All of the aforementioned factors offer a convincing argument to pursue early evaluation of young children following their first documented UTI. Waiting until these children have had two or more UTIs before proceeding with evaluation clearly increases the risk that permanent scarring, which might have otherwise been prevented, may occur. Imaging children with their first documented UTI should be pursued in all boys and in all girls fewer than 5 years of age. Furthermore, all older girls with febrile or recurrent infections also should be evaluated. As a result of the decreased incidence of VUR in the black population; evaluation in black girls might well be reserved for infants and patients with febrile infection or frequent recurrences. Evaluation should focus on early identification of patients at risk for renal damage or conditions that would predispose a child to recurrent infections. Practicality limits the evaluation to the investigation of etiologic parameters that can be modified to decrease or eliminate the morbidity of infections.

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RUSHTON

60

50

40

.-

30

L

3

s-

(II

c Q)

U

20

c, .3

8 10

0

-*4

0

(11441)

(n=366)

(n=98)

(n=35)

(n=24)

# of episodes acute pyelonephritis Figure 8. Relationship of renal scarring to number of episodes of acute pyelonephritis. (Adapted from Jodal U: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1:713,1987.)

History Evaluation of children with UTIs begins with a careful history. Because bladder emptying plays an important role in the cause and prevention of UTI, a careful voiding history is an essential component of the workup of toilet-trained children with UTIs. A voiding and bowel habit diary kept by the parents can be very helpful in identifying children with underlying voiding dysfunction, particularly in children with recurrent UTIs. Family history also should be obtained. Heredity seems to play a role in an individual’s predisposition to infection as

URINARY TRACT INFECTIONS IN CHILDREN

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evidenced by familial studies showing an increased incidence of bacteriuria in female siblings.23Similarly, a significant familial risk for VUR has been demonstrated when a sibling or parent has a history of re flu^.^^

Physical Examination Physical examination of children presenting with UTIs should include palpation of the abdomen for flank masses, bladder distension, or abdominal masses caused by fecal impaction. Although genital examination in boys should exclude significant meatal stentosis, this is an extremely rare cause of UTIs. Considering the epidemiologic evidence demonstrating an increased risk for UTIs in uncircumcised boys, the circumcision status is of particular importance in male infants. Abnormal genital findings in girls include vulvovaginitis or the presence of labial adhesions, which might predispose children to perineal colonization by bacteria. More often labial adhesions increase the likelihood (or risk) for contamination of "clean-catch'' urine specimens for culture. In children with a significant history of voiding dysfunction associated with constipation or encopresis, a brief neurologic examination should include evaluation of perineal sensation, checking of peripheral reflexes in the lower extremities, and examination of the lower back for sacral dimpling or cutaneous abnormalities suggestive of an underlying spinal abnormality (e.g., occult spinal dysraphism). Rectal examination for fecal impaction is indicated if the history suggests severe constipation or encopresis.

Imaging Recommended imaging studies for children with a history of culture-documented UTIs are based, to some extent, on the experience of the radiologist and the availability of imaging modalities. The timing of evaluation is often a concern of pediatricians, radiologists, and pediatric urologists. Children requiring hospitalization for febrile infections should at least be screened for obstruction with sonography before discharge. It has been suggested that cystography be delayed 4 to 6 weeks following the acute infection to avoid demonstrating transient mild reflux secondary to inflammatory changes of the ureterovesical junction; however, it is rare for reflux to be detected during infection and then to disappear after treatment.31Furthermore, because the significance of reflux is greatest at the time of bacterial infection, demonstration of even transient reflux may be very meaningful. One potential disadvantage of obtaining a cystogram early in the early course of a febrile infection is that ureteral dilatation secondary to the effect of endotoxins may result in overestimation of the grade of re flu^.^^ Nevertheless, a prolonged waiting period is not necessary. The cystogram can be performed whenever the patient is no longer symptomatic and when the urine is Regardless of when imaging studies are performed,

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RUSHTON

antibiotic prophylaxis should be maintained until that time, particularly in infants or children with a history of previous febrile UTIs, to prevent reinfection. Cystography in girls and boys may be reserved for children fewer than 5 years of age with their first documented UTI and for older children with febrile UTIs or recurrent infections. In older boys with their first episode of cystitis, a sonogram of the kidneys and bladder suffices if negative; however, if hydronephrosis or significant bladder wall thickening is found, a voiding cystogram to exclude bladder outlet obstruction is mandatory. In boys a contrast voiding cystourethrogram (as opposed to an isotope cystogram) with a preliminary radiograph (plain film) is indicated to exclude urethral pathology as well as to identify VUR. The plain film allows for inspection of the spine and demonstrates the amount of stool in the colon. Because visualization of the urethra is rarely helpful in girls, except in unusual cases of refluxing ectopic ureters, either a contrast or isotope cystogram may be obtained. A contrast cystogram does afford the opportunity to more precisely determine the severity of the reflux, if present. Several classifications have been used to grade VUR. The scheme shown in Figure 9 is widely accepted and was endorsed by the International 135 Isotope cystography is associated with reduced radiaReflux tion exposure to the gonads and allows for continuous monitoring throughout the study, which may increase the sensitivity of the study

I

I1

Iv

V

Figure 9. International classification of vesicoureteral reflux. Grade I,ureter only; Grade I/, ureter, pelvis, calyces; no dilatation, normal calyceal fornices; Grade I//, mild or moderate dilatation and/or tortuosity of ureter, and mild or moderate dilatation of the pelvis, but no or slight blunting of the fornices; Grade IV, moderate dilatation and/or tortuosity of ureter, and mild dilatation of renal pelvis and calyces; complete obliteration of sharp angle of fornices, but maintenance of papillary impressions in majority of calyces; Grade V, gross dilatation and tortuosity of ureter; gross dilatation of renal pelvis and calyces; papillary impressions are no longer visible in majority of calyces. (Adapted from International Reflux Committee: Medical versus surgical treatment of primary vesicoureteral reflux. Pediatrics 67:392,1981; with permission.)

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1157

for the detection of transient re flu^.'^^ For these reasons, it is the best choice for a follow-up evaluation of children with known reflux and in documenting the results of antireflux surgery. It is also the recommended study of choice for screening for sibling reflux. Recommendations for evaluating the upper urinary tract in children presenting with UTIs vary from institution to institution. The ideal study would be painless, safe, cost effective, and associated with minimal or no radiation and yet be capable of detecting all clinically significant structural malformations as well as renal scarring. Unfortunately, such an all-encompassing study is not currently available. One approach to upper tract imaging is to initially screen all patients being evaluated for urinary infection with a renal-bladder s o n ~ g r a mIn . ~children, ~ sonography has been found to be as sensitive as IVP for the detection of significant renal abnormalities other than uncomplicated duplication 5y Sonography is painless, noninvasive, simple and focal renal to perform, radiation free, and independent of renal function. It is critical that appropriate images of the ureters, bladder, and true pelvis be routinely obtained to detect the presence of ureteroceles or dilated ureters secondary to ureteral ectopia, ureterovesical junction obstruction, or severe VUR. Bladder wall thickening and trabeculation associated with hypertrophy of the detrusor muscle in children with obstruction or severe voiding dysfunction also can be ascertained. To do so, the bladder should be full during the examination. Postvoiding residual urine also can be demonstrated at the completion of the study, although its significance in this stressful situation should be questioned. In most cases no further imaging is required if the cystogram and renal-bladder sonogram are normal. Similarly, cystoscopy no longer plays a diagnostic role in the routine evaluation of children with UTIs. Children who are found to have VUR are further evaluated with a cortical renal scan, using either 9ymTc DMSA or glucoheptonate. DMSA scintigraphy is not only more sensitive and specific than IVP for the detection of renal scarring but also it is capable of providing quantitative assessment of differential renal function (Fig. 28, 86, 88* 118,lZ7 Therefore, DMSA scintigraphy in patients with VUR allows for the detection of renal damage at the time of initial evaluation and serves as a baseline for follow-up in patients managed nonoperatively in the event that a breakthrough infection occurs. Not all patients with reflux and breakthrough UTIs require immediate surgery; however, when new renal damage is objectively demonstrated by a DMSA scan, antireflux surgery is imperative. DMSA scintigraphy is also important in the initial evaluation of infants with prenatally detected VUR because some of these patients with high-grade W R have significant congenital reflux nephropathy, even in the absence of infe~tion.~, 29, Renal cortical scanning with DMSA or glucoheptonate is also an excellent means of evaluating children with acute febrile UTIs who are suspected of having pyelonephritis (Fig. 11). Previous experimental studies have demonstrated that DMSA scintigraphy is highly sensitive for the detection and localizaton of acute pyelonephritis in young pigs, @

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RUSHTON

Figure 10. 99mTc-dimercapto~~ccinic acid renal scan in a 7-year-old girl 7 months after her first documented febrile urinary tract infection. A voiding cystogram revealed bilateral grade IIN vesicoureteral reflux. Renal scarring is present in both kidneys. The left upper pole is flattened. There is a wedge-shaped defect in the right lower pole and thinning of the right upper pole. (From Rushton HG: Reflux versus nonreflux pyelonephritis: Is there a difference? In Gonzales ET, Jr, Paulson DF (eds): Problems in Urology: Advances in Pediatric Urology, vol 8. Philadelphia, JB Lippincott, 1994; with permission.)

animals with the same papillary renal architecture as h~mans.9~3 114 Prospective studies comparing sonography with DMSA renal scans in children with febrile UTIs consistently have reported much higher sensitivity for DMSA scintigraphy in the detection of acute pyelonephritis.6,9, 78, 144 DMSA scans at the time of breakthrough infection in patients with VUR identify those at risk for renal scarring resulting from that episode. In patients without VUR, use of DMSA scintigraphy is best reserved for occasions when it influences management. It is particuarly helpful for establishing the correct diagnosis of acute pyelonephritis when this is unclear based on clinical and laboratory findings. For example, neonates and young infants with UTI frequently present with nonspecific signs and symptoms. Urine cultures are not always obtained properly or before starting antibiotics, resulting in ambiguous results. DMSA scans also can be very helpful in the evaluation of febrile episodes in children with spina bifida whose bladders are managed by clean intermittent catheterization. Chronic ABU is common in this group, thus limiting the diagnostic potential of a positive urine culture when these patients present with unexplained fever. Finally, the finding of direct scintigraphic evidence of renal parenchymal involvement at the time of acute pyelonephritis may be an important determinant of the need for antibiotic prophylaxis in some children, such as in neonates and infants or in patients with recurrent UTIs.

URINARY TRACT INFECTIONS IN CHILDREN

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Figure 11. Two-year-old girl with febrile urinary tract infection. 99mTc-dimercaptosuccinic acid scan reveals diminished uptake of isotope in left upper pole (posterior oblique view) with preservation of the renal contour. These are typical DMSA scan findings of acute pyelonephritis. (From Rushton HG: Reflux versus nonreflux pyelonephritis: Is there a difference? In Gonzales ET, Jr, Paulson DF (eds): Problems in Urology: Advances in Pediatric Urology, vol 8. Philadelphia, JB Lippincott, 1994; with permission.)

When hydronephrosis in the absence of VUR is demonstrated by sonography, further evaluation with diuretic renography using 99mT~labeled diethylenetriamine-pentaacetic acid (DTPA) or mercaptoacetyltriglycine (MAG-3) provides quantitative assessment of renal function and drainage of the dilated collecting system.6O Evaluation of these two parameters objectively differentiates nonobstructive dilatation from true obstruction. When combined with the findings of the renal-bladder sonogram, the site of obstruction can be determined reliably in almost all cases. TREATMENT

The obvious goals of treatment of UTIs are to provide symptomatic relief and prevent both further UTIs and new or progressive renal damage. Initial treatment, ideally, should be based on urine cultures to document UTIs (colony count) and to provide sensitivities. Frequently, such testing is not done or treatment is instituted before the culture results are available. Fortunately, because the common uropathogens are susceptible to multiple antibiotics and the response to antibiotics correlates best with urine levels that are usually more highly concen-

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RUSHTON

trated than serum levels, high cure rates have been reported in most therapeutic trials.

Cystitis

Agents that have been used successfully for acute, uncomplicated lower urinary infections include sulfonamides, trimethoprim-sulfamethoxazole (TMP-SMX), nitrofurantoin, trimethoprim, and oral cephalosporins. Unfortunately, ampicillin and amoxicillin are used commonly by primary health care physicians, and resistant organisms are common.61 Although this drawback has been diminished by the relatively recent combination of clavulanic acid with amoxicillin, this antibiotic is associated with a higher incidence of side effects, is expensive, and is no more effective than the usual drugs. The optimal duration of treatment of acute uncomplicated lower UTIs in children is controversial. Several randomized, controlled studies have been published reporting the use of single-dose or short-course antmicrobial therapy in children. The potential advantages of shortcourse therapy include decreased costs, improved compliance, decreased side effects, and decreased effect on the fecal flora. Moffatt and associa t e reported ~ ~ ~ a methodologic analysis of 14 published randomized, controlled trials of short-course antimicrobial therapy for uncomplicated lower UTIs in children. Short-course therapy varied in these studies, with nine using single-dose, one using 1-day, three using 3-day, and one using 4-day treatment. Conventional therapy ranged from 7 to 10 days. In two, short-course therapy was less effective, including one that compared single-dose versus 10-day amoxicillin therapy and one that compared 1-day versus 10-day cefadroxil therapy. The other 12 studies showed no significant difference in outcome; however, small sample size was a major methodologic flaw in all except the two that reported a decreased efficacy in short-course treatment. The authors concluded that there is still insufficient evidence to recommend short-course therapy for UTIs in children. In a subsequent review article recently published by Khan,61 the findings in 12 of these reports were reevaluated by pooling the data on 320 infants and children. He reported that single-dose therapy achieved an overall cure rate of 89% (63-100%); however, the response varied with the antimicrobial agents. Intramuscular aminoglycosides, achieved the highest cure rate (96%), followed by TMP-SMX or a sulfa drug (90%). The cure rate of amoxicillin was significantly less (75%). Single-dose therapy was most effective in patients with a well-documented lower UTI and in children with an anatomically normal urinary tract. Two additional large clinical studies have investigated short-course versus 10-day antibiotic therapy in children with lower uncomplicated UTIs. In one there was no difference in the bacteriologic cure rate for single-dose (93%) versus multidose regimens (96%), but short-term

URINARY TRACT INFECTIONS IN CHILDREN

1161

recurrence rates after treatment were significantly higher in the singledose group (20.5%) compared with the 3-day (5.6%) and 7-day (8%) groups.79Similar results with short-course therapy were observed in a prospective, randomized, open multicenter study of 264 girls 1 to 15 years old when short-course treatment with 3 days of either sulfamethizole or pivmecillinam was compared with 10 days' treatment of sulfam e t h i z ~ l e In . ~ ~this study, there was no difference between 3- and 10day therapy in the number of girls with negative urine cultures after treatment or in the recurrence-free interval. Based on the existing data, it would seem reasonable to treat acute lower uncomplicated UTIs in children with a "relatively" short 3- to 5day course of antibiotics; however, children less than 5 years old who have not been previously evaluated should then continue to receive lowdose antimicrobial prophylaxis until radiographic evaluation is completed.

Pyelonephritis Children with suspected acute pyelonephritis require a greater degree of assurance of immediate therapeutic success because the degree of scarring and renal damage from an infection may be influenced by the rapidity of effective therapy. In a recently published retrospective study of 52 children 1 to 12 years of age with bilateral severe VUR and bilateral renal scarring, the severity of renal scarring was related significantly to a delay in the diagnosis and treatment of UTIS.'~~ Although most would concur with a 10- to 14-day course of antibiotic therapy for pyelonephritis, there is considerable controversy over the need for hospitalization and treatment with parenteral antibiotics versus outpatient therapy with oral drugs. In a recent survey of 445 general practitioners, 143 pediatricians, and 45 pediatric nephrologists, significant differences were found in the recommendation for initial hospitalization by the general practitioners and pediatricians (17%) compared with the pediatric nephrologists (69%).16The pediatric nephrologists were evenly split between single and combined antibiotic therapy, whereas general practitioners and pediatricians preferred monotherapy. Intravenous antibiotics were preferred by 78% of the pediatric nephrologists compared with only 23% to 27% of pediatricians and general practitioners. This may suggest a greater concern and awareness on the part of the nephrologists regarding the potential for renal damage associated with pyelonephritis in children. Clearly, there is a need for controlled therapeutic trials for UTIs in children with old and new drugs in different dosages and for varying lengths of treatment.37These trials should categorize patients into different age groups, such as: (1) neonates aged 0 to 28 days; (2) infants aged 1 month to less than 2 years; (3) older children more than 2 years of age; and (4) adolescent^.^^ Meanwhile, until such clinical trials are conducted, nontoxic children and infants more than 3 months of age can

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be treated as outpatients as long as compliance is not an issue. It is reasonable to initiate therapy with 1 to 2 days of a long-acting, thirdgeneration cephalosporin, such as ceftriaxone, administered intramuscularly, followed by 10 to 14 days of oral antibiotics and prophylaxis until evaluated. This approach virtually ensures compliance and adequate antimicrobial coverage until the urine culture and sensitivity results are known. Alternatively, if compliance does not seem to be a problem, initial therapy with appropriate, broad-spectrum oral antibiotics may be as effective in the treatment of acute pyelonephritis and in the prevention of irreversible renal damage.42 In contrast, toxic children and infants less than 3 months of age with suspected acute pyelonephritis should be considered candidates for immediate hospitalization and parenteral therapy. In these patients, combination therapy, including an aminoglycoside and ampicillin, are appropriate choices until the urine culture results are known. Alternatively, one of the newer third-generation cephalosporins may be used, but these are more expensive and do not provide comprehensive coverage of gram-positive organisms, including enterococcus. Parenteral antibiotic therapy should be continued for 7 to 14 days in neonates, although oral outpatient therapy to complete a full 10- to 14-day course can be substituted in patients more than 2 months of age when afebrile for 24 to 48 hours. Asymptomatic Bacteriuria Antibiotic treatment of ABU does not seem necessary if a child’s voiding habits and urinary tract are otherwise normal.20,136 Others have questioned the need for treatment even in the presence of renal scarring, suggesting that ABU caused by bacterial mutants with low virulence seem to protect against infection with virulent strains.51,73 The risk for pyelonephritis in infants and young girls with untreated ABU is small, and many demonstrate spontaneous remission, particuarly after achieving normal voiding habits.51,140 In contrast, treatment of patients with ABU is followed by a high recurrence rate, most being caused by new strains that may carry the risk of being more virulent. It is important to distinguish between children with isolated ABU and children who have previously undiagnosed voiding disorders, including infrequent voiding. Children with voiding disorders are usually not truly asymptomatic. Therefore, combined treatment of the voiding disorder and bacteruria followed by long-term antibiotic prophylaxis may be necessary. Likewise, it is equally important to identify children who may present with fever and a coincidental but unrelated positive urine culture. In these patients, fever is not a consequence of the UTI, such as is often the case in children with spina bifida managed with clean intermittent catheterization (CIC). Again, in this situation DMSA scans can be very helpful in differentiating children with pyelonephritis from children with fever and coincidental bacteriuria.

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Antibiotic Prophylaxis

Long-term, continuous antibiotic prophylaxis is recommended for children with known VUR. Although most practitioners prefer to continue antibiotic prophylaxis until the reflux either resolves spontaneously or is corrected surgically, some investigators have questioned the need for this, particuarly in low-risk patients, such as boys more than 1 to 1.5 years of age and older girls with lower grades of pesistent re flu^.'^^ For a more detailed discussion of the use of antibiotic prophylaxis in the management of children with VUR, the reader is referred to the article by Belman in this issue. Other indications for long-term prophylaxis include children with frequent symptomatic recurrences (> 3 per year), particularly when these are associated with underlying bladder instabilty or abnormal voiding patterns. In addition to appropriate antimicrobial therapy, successful treatment of underlying voiding disorders and constipation is an essential component of their management. In children with small-capacity, uninhibited bladders, treatment with an anticholinergic coupled with a timed voiding schedule usually is required. In older girls with recurrent UTIs associated with infrequent voiding and a large-capacity bladder, the mainstay of treatment is a timed voiding schedule and appropriate bowel regimen. For a more detailed discussion of the evaluation and management of voiding disorders in children, the reader is referred to the article by Wan and Greenfield in this issue. Antibiotic prophylaxis should also be considered in neonates and infants less than 1 year of age who present with a febrile UTI associated with evidence of acute inflammatory damage on DMSA renal scans. Approximately one third of these childeren are at risk for symptomatic recurrences, more than 90% of which are clinically consistent with pyelonephritis. SUMMARY

Accurate documentation of UTIs in children is essential for proper evaluation and management. Urine cultures with multiple organisms or colony counts less than 50,000 to 100,000 CFU/ml should be considered suspect and require confirmation, particularly with clean-catch specimens. Children with well-documented UTIs should be evaluated based on their age and presenting symptoms. Infants and young children require imaging, usually with a cystogram and sonogram of the kidneys and bladder. Older girls with febrile UTIs and boys at any age should also be considered for urinary tract imaging. Renal cortical scintigraphy with 99mTc-DMSA has emerged as the imaging study of choice for acute pyelonephritis and renal scarring in children with UTIs. Treatment of UTIs in children ideally commences with culturespecific antimicrobial therapy, although treatment may be started in sick children before culture results are available. Short-course treatment (3-5 days) is sufficient for children with acute uncomplicated lower UTIs.

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Children with acute pyelonephritis require 10 to 14 days of antibiotics, which can be administered on an outpatient basis in older infants and children who are not toxic, as long as good compliance is expected. Patients with first-time UTIs who require imaging should be maintained on low-dose antibiotic prophylaxis until their workup is completed. Treatment of ABU does not seem necessary if the urinary tract is otherwise normal. Long-term antibiotic prophylaxis is indicated for children with frequent symptomatic recurrences of UTI and for those with known VUR. Diagnosis and treatment of underlying voiding dysfunction and constipation is an essential component of the successful management of UTIs in children.

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