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.Infertilidade
.Disfunção erétil
.Infecção urinária
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HPV na Prática Clínica

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 JONATHAN H. ROSS, M.D., and ROBERT KAY, M.D.
Cleveland Clinic Foundation
Cleveland, Ohio

Urinary tract infections in children are sometimes associated with vesicoureteral reflux, which can lead to renal scarring if it remains unrecognized. Since the risk of renal scarring is greatest in infants, any child who presents with a urinary tract infection prior to toilet training should be evaluated for the presence of reflux. Children who may be lost to follow-up and those who have recurrent urinary tract infections should also be evaluated. The preferred method for evaluation of urinary reflux is a voiding cystourethrogram. Documented reflux is initially treated with prophylactic antibiotics. Patients who have breakthrough infections on prophylaxis, develop new renal scarring, have high-grade reflux or cannot comply with long-term antibiotic prophylaxis should be considered for surgical correction. The preferred method of surgery is ureteral reimplantation. A newer method involves injection of the bladder trigone with collagen.
Urinary tract infections in children are a significant source of morbidity, particularly when associated with anatomic abnormalities.1 Vesicoureteral reflux is the most commonly associated abnormality, and reflux nephropathy is an important cause of end-stage renal disease in children and adolescents.2 However, when reflux is recognized early and managed appropriately, renal insufficiency is rare. Some children who present with an apparently uncomplicated first urinary tract infection turn out to have significant reflux. Subclinical infections can sometimes lead to severe bilateral renal scarring. Therefore, even a single documented urinary tract infection in a child must be taken seriously.

Diagnosis
Children with urinary tract infections do not always present with symptoms such as frequency, dysuria or flank pain. Infants may present with fever and irritability or other subtle symptoms, such as lethargy. Older children may also have nonspecific symptoms, such as abdominal pain or unexplained fever. A urinalysis should be obtained in a child with unexplained fever or symptoms that suggest a urinary tract infection. In young children with urinary tract infections, urinalysis may be negative in 20 percent of cases. Barnaff and colleagues3 recommend a urine culture for all male patients under six months of age and all female patients under two years of age who have a temperature of 39°C (102.2°F) or higher. Because a documented infection may warrant a thorough radiographic evaluation, empiric treatment on the basis of symptoms or urinalysis alone should be avoided.

While the most reliable method of obtaining urine for a culture is suprapubic aspiration, this procedure often causes anxiety in the child, the parent and the physician. Urine specimens may therefore be obtained by placing a plastic bag over the perineum of infants, and by obtaining a voided specimen in older children. Because "bagged" and voided specimens may be contaminated, results must be interpreted in conjunction with the urinalysis and the clinical setting. Pyuria and/or classic symptoms support the diagnosis of a urinary tract infection, whereas a positive culture in a child with a normal urinalysis and/or atypical symptoms may represent contamination. In patients whose diagnosis is complicated, and when the uncertainty of contamination must be avoided, a catheterized or suprapubic specimen can be obtained. Because catheterization may introduce bacteria into the bladder, a single dose of oral antibiotic should be given to prevent iatrogenic infection.
While the presence or absence of a true urinary tract infection is occasionally difficult to determine, the distinction between cystitis and pyelonephritis is even more problematic. No clinical findings (such as fever or flank pain) and no laboratory studies (such as erythrocyte sedimentation rate or white blood cell count) are accurate in distinguishing pyelonephritis from cystitis.4 Fortunately, this distinction is rarely crucial. The management of the child is dictated by the clinical severity of the illness, rather than by the specific site of infection in the urinary tract. Furthermore, since the risk of reflux is similar in all patients with a urinary tract infection, the distinction between cystitis and pyelonephritis is not important in guiding the need for radiographic evaluation.
In rare circumstances, when distinguishing the diagnosis of pyelonephritis from some other infection is important, a technetium-99m dimercaptosuccinic acid (DMSA) renal flow scan is the best study to obtain.5 Patients with a normal scan during an acute infection do not have pyelonephritis and will not develop scarring. However, an area of photopenia on a DMSA scan identifies a region of pyelonephritis that is at risk for eventual scar formation (Figure 1). Because this test is invasive, expensive, exposes the child to radiation and is unlikely to alter the management of the infection, it is not used in the routine evaluation of children with urinary tract infections.

Evaluation
The most significant anomaly associated with urinary tract infections in children is vesicoureteral reflux, which occurs in 30 to 50 percent of these patients.6 Despite the high rate of association, no randomized prospective studies demonstrate the benefit of screening these patients for anomalies.7 However, there is no doubt that vesicoureteral reflux is associated with renal scarring, in part because it allows lower tract infections to ascend, resulting in pyelonephritis.5

Since antibiotic prophylaxis can prevent recurrent urinary tract infections, it seems prudent to screen children with urinary tract infections who are at risk for renal scarring, such as children with recurrent urinary tract infections. Since children are at greatest risk for renal scarring in the first few years of life, reflux screening is recommended for any child who has a single urinary tract infection before toilet training has begun. Older children who receive consistent medical care (in whom a pattern of recurrent urinary tract infections would not be missed) may not need to be screened following a single infection. An alternative to more invasive screening might be renal ultrasonography. Although ultrasonography is a poor screening test for reflux, missed reflux may be of little concern in an older child with a single infection and normal results on renal ultrasound examination.
When a child is screened for reflux, the appropriate test to obtain is a cystogram. A cystogram performed by an experienced pediatric radiologist is well-tolerated by most children. Although renal ultrasound examinations are less invasive, they are normal in 50 to 75 percent of patients with reflux and, therefore, are ineffective for screening.8 A DMSA renal scan is the best study for detecting renal scarring and might therefore identify patients at particular risk for reflux. Unfortunately, a renal scan will not detect reflux in children who have not yet developed scarring, and these are the very ones who might benefit most from antibiotic prophylaxis.
Obtaining a cystogram in a patient with a urinary tract infection should be delayed for at least 48 hours after initiating antibiotic therapy so as not to induce bacteremia by instrumenting the urinary tract. It is not necessary to delay the cystogram beyond this point. Concern that obtaining a cystogram too soon after a urinary tract infection may result in a false-positive study is ill-founded. Even children who have reflux only when they have cystitis have a significant problem, since reflux causes scarring by allowing cystitis to ascend.5

FIGURE 2. Voiding cystourethrogram revealing bilateral grade 3 reflux into small, scarred kidneys.

A renal ultrasound examination may also be obtained to rule out obstructive uropathy in children. An ultrasound examination can detect gross renal scarring or marked asymmetry of renal size in patients with vesicoureteral reflux. A DMSA renal scan is the best method for detecting renal scarring.9
Two types of cystogram are available. A standard voiding cystourethrogram (VCUG) is obtained by instilling radiopaque contrast medium into the bladder and imaging the bladder and renal fossae during filling and voiding (Figure 2). The severity of vesicoureteral reflux is graded on a scale of 1 to 5, depending on the degree of distention of the collecting system.
A nuclear cystogram can be obtained by instilling a radionuclide agent into the bladder and imaging with a gamma camera. Nuclear cystography is at least as sensitive for the detection of reflux as a standard VCUG and exposes the child to less radiation.10 However, grading of reflux is less precise, and associated bladder abnormalities cannot be detected with nuclear cystography. Therefore, a VCUG is preferred as the initial study in the evaluation of a child with a urinary tract infection. Nuclear cystography is used in follow-up of patients with vesicoureteral reflux who are on an observation protocol. Vesicoureteral reflux is present in one third of siblings of patients with reflux, and in two thirds of the children of patients with reflux.11,12 Nuclear cystography may be employed for screening these children as well.

Treatment
Because urinary tract infections are usually caused by gram-negative rods, particularly Escherichia coli, any oral antibiotic with good gram-negative coverage is a reasonable choice for treatment. Trimethoprim/sulfamethoxazole (Bactrim, Spectra) offers good coverage and is inexpensive. It is given in suspension form in a dosage of 4 mg trimethoprim per kg twice daily. Other commonly used antibiotics include amoxicillin, in a dosage of 10 mg per kg three times daily, and nitrofurantoin (Furadantin, Macrodantin, Macrobid), in a dosage of 2.5 mg per kg three times daily. Cephalosporins may be indicated if infection with a more resistant organism is suspected. Ciprofloxacin (Cipro) is not approved for use in children. However, carbenicillin is available in an oral form for treating uncomplicated cystitis that is caused by susceptible strains of Pseudomonas.
Children who require hospitalization should be placed on broad-spectrum intravenous antibiotics pending the results of the urine culture. Because most community-acquired urinary tract infections are caused by gram-negative bacilli, coverage should include an aminoglycoside, a cephalosporin or a broad-spectrum penicillin derivative. Coverage may need to be broader in children who have recently been hospitalized or who have had recent instrumentation or recurrent infections, since they may be infected with gram-positive organisms such as Enterococcus or coagulase-negative Staphylococcus. A urine gram-stain may be helpful in the initial selection of antibiotics. An algorithm showing the evaluation and management of a child with a urinary tract infection is presented in Figure 3.

Management of Urinary Tract Infection

Management of Vesicoureteral Reflux
Reflux resolves spontaneously in some patients. It is more likely to resolve if it is low-grade, unilateral and not associated with anomalies. The grade of reflux is the most important factor. Over several years of observation, reflux resolves in approximately 80 percent of patients with grade 1 or grade 2 reflux, 50 percent of patients with grade 3 reflux and 25 percent of patients with grade 4 reflux.13 Because of this tendency to resolve, most patients with reflux are initially treated on an observation protocol.

The current management of reflux is based on direct and indirect scientific data, as well as a traditional standard of care. With this in mind, the American Urological Association recently developed clinical practice guidelines for the management of reflux.14 Because renal scarring usually occurs only with the reflux of infected urine, the prevention of urinary tract infections in children with reflux is essential, and the mainstay of medical management is antibiotic prophylaxis. The most frequently used agents are nitrofurantoin, in a dosage of 1 to 2 mg per kg once daily, and trimethoprim/sulfamethoxazole, in a dosage of 2 to 4 mg trimethoprim per kg once daily.
In patients under observation, periodic urine cultures should be obtained (approximately every three months) to detect asymptomatic bacteriuria. Follow-up cystograms are obtained annually, and prophylaxis is discontinued when reflux resolves. Upper tract studies are obtained periodically as dictated by the patient's clinical course. Bladder instability and constipation can predispose a child to urinary tract infections and exacerbate reflux.15-20 The presence of these symptoms should be actively determined and promptly treated.
Any patient under observation who develops a break-through urinary tract infection or new renal scarring should undergo surgical correction of reflux. Surgery is also appropriate in patients who cannot comply with close follow-up and long-term antibiotic prophylaxis. This includes patients who wish to avoid repeat cystograms and office visits. Patients with high-grade reflux may be considered for immediate surgical intervention.
The standard operation for vesicoureteral reflux is ureteral reimplantation, which is successful in 95 percent of cases.21 Although antireflux surgery effectively reduces the risk of pyelonephritis, approximately one third of the children will continue to have cystitis.21
The subtrigonal injection of collagen is a relatively new alternative treatment for vesicoureteral reflux. This technique is performed as an outpatient cystoscopic procedure under a brief general anesthetic. It involves significantly less morbidity than the standard operation but is successful in only 65 to 70 percent of cases.22,23 The long-term efficacy of collagen injection has not yet been determined.

Recurrent Urinary Tract Infections
Some children without a discernable anatomic anomaly develop recurrent urinary tract infections. Many of these children present after toilet training, when normal spontaneous voiding is prevented by social constraints. The risk of renal scarring in these patients is low, but not absent. Some of these children have symptoms of bladder instability, such as urge incontinence or squatting behavior, in the absence of an infection. Bladder instability may be improved by placing the child on a timed voiding schedule of once every three hours. If behavioral approaches fail, voiding symptoms often respond to anticholinergic agents such as oxybutynin (Ditropan), in a dosage of 0.15 mg per kg three times daily. Even when the symptoms are subtle and not in and of themselves troublesome, the recurrent infections can be prevented or reduced in frequency by employing anticholinergic therapy in conjunction with antibiotic prophylaxis. Constipation can also predispose to bladder instability and recurrent urinary tract infections and should therefore be aggressively managed.19,20

Even an anatomically and functionally normal urinary tract may be predisposed to recurrent infections. Certain host factors may play a role, such as antigen expression on the bladder epithelium.24 However, there is no specific therapy for these host factors, so children with frequent infections are managed with antibiotic prophylaxis administered in the same fashion as in patients with vesicoureteral reflux. However, in the absence of reflux, upper tract monitoring and routine urine cultures are rarely indicated. Treatment of asymptomatic bacteriuria in this setting is unnecessary.

The Foreskin and Urinary Tract Infections
A resurgence of sentiment favoring routine neonatal circumcision has occurred in the last decade because of recently described associations between an intact foreskin and urinary tract infections in infants. This association was best illustrated in a series of systematic studies by Wiswell and associates25-28 at U.S. Army hospitals. In several large epidemiologic studies, the authors found that the incidence of significant urinary tract infections in uncircumcised males less than six months of age was 1 to 4 percent. The incidence in circumcised males was only 0.1 to 0.2 percent.
Because of the data demonstrating an increase in the rate of infection, routine circumcision has been advocated by some authors. They point out the significant mortality and renal scarring associated with urinary tract infections occurring in early infancy. However, circumcision is a permanent solution to a problem that affects males only during the first six months of life. There may be alternative, nonsurgical means of preventing these infections, and the question of whether all boys should be circumcised to prevent infection in 1 to 4 percent remains debatable. It is also unclear whether circumcision would augment the benefit of antibiotic prophylaxis in boys with reflux or other urologic anomalies.
Figure 1 reprinted with permission from Rushton HG, Majd M. Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J Urol 1992;148(5 Pt 2):1726-32.

The Authors
JONATHAN H. ROSS, M.D.,
is a member of the Section of Pediatric Urology in the Department of Urology at the Cleveland (Ohio) Clinic Foundation. He received his medical degree from the University of Michigan Medical School, Ann Arbor, and completed a residency in urology at the Cleveland Clinic Foundation. Dr. Ross also completed a fellowship in pediatric urology at the Children's Hospital of Michigan, Detroit.
ROBERT KAY, M.D.,
is a member of the Section of Pediatric Urology in the Department of Urology at the Cleveland Clinic Foundation. He graduated from the University of California, Los Angeles, UCLA School of Medicine, and completed a residency in urology at the Oregon Health Sciences University School of Medicine, Portland, and a fellowship in pediatric urology at Alder Hey Children's Hospital, Liverpool, England. He is past president of the Urologic Section of the American Academy of Pediatrics.
Address correspondence to Jonathan

Evaluation and Treatment of Urinary Tract Infections in Children

SYED M. AHMED, M.D., M.P.H., D.P.H., and STEVEN K. SWEDLUND, M.D.
Wright State University School of Medicine, Dayton, Ohio

Urinary tract infections (UTIs) are among the most common bacterial infections encountered by primary care physicians. Although UTIs do not occur with as great a frequency in children as in adults, they can be a source of significant morbidity in children. For reasons that are not yet completely understood, a minority of UTIs in children progress to renal scarring, hypertension and renal insufficiency. Clinical presentation of UTI in children may be nonspecific, and the appropriateness of certain diagnostic tests remains controversial. The diagnostic work-up should be tailored to uncover functional and structural abnormalities such as dysfunctional voiding, vesicoureteral reflux and obstructive uropathy. A more aggressive work-up, including renal cortical scintigraphy, ultrasound and voiding cystourethrography, is recommended for patients at greater risk for pyelonephritis and renal scarring, including infants less than one year of age and all children who have systemic signs of infection concomitant with a UTI. Antibiotic prophylaxis is used in patients with reflux or recurrent UTI who are at greater risk for subsequent infections and complications.
Urinary tract infection (UTI) is defined as the presence of bacteria in urine along with symptoms of infection. UTIs occur in as many as 5 percent of girls and 1 to 2 percent of boys.1 The incidence of UTI in infants ranges from approximately 0.1 to 1.0 percent in all newborn infants to as high as 10 percent in low-birth-weight infants.2 Infection of the urinary tract before age one occurs more frequently in boys than in girls.2 After age one, both bacteriuria and UTI are more common in girls.
In preschool-age children, the prevalence of asymptomatic infections diagnosed by suprapubic aspiration in girls is 0.8 percent, compared with 0.2 percent in boys.3 In the school-age group, the incidence of bacteriuria among girls is 30 times that among boys (1.2 versus 0.04 percent).4

Etiology and Pathogenesis
Escherichia coli is the most common infecting pathogen in children, accounting for up to 80 percent of UTIs. Other pathogens include Staphylococcus and Streptococcus species, a variety of enterobacteria (e.g., Klebsiella, Proteus) and, occasionally, Candida albicans. The virulence of the invading bacteria and the susceptibility of the host are of primary importance in the development of UTI.3 In neonates, the usual route of infection is presumed to be hematogenous.1 Later in life, infection is usually caused by ascension of bacteria into the urinary tract.5

FIGURE 1. Relationship between urinary tract infection and loss of renal function.

Any condition that leads to urinary stasis (renal calculi, obstructive uropathy, vesicoureteral reflux and voiding disorders) may predispose to the development of UTI in children.5 Renal parenchymal infection and scarring are well-established complications of infection of the upper urinary tract in children and can lead to renal insufficiency, hypertension and renal failure. Parenchymal scarring develops in 10 to 15 percent of children with UTI. Children less than one year of age with a UTI are at much greater risk for renal scarring than older children; children over five years of age uncommonly have new renal scarring with UTI.6 A 27-year follow-up study from Sweden1 showed that focal renal scarring caused by pyelonephritis in a child carried a 23 percent risk for hypertension and a 10 percent risk for end-stage renal disease.
Controversy continues regarding the association of vesicoureteral reflux with the pathogenesis of renal scarring, reflux nephropathy, pyelonephritis and voiding disorders. Although vesicoureteral reflux is associated with renal scarring,7 its role in the pathogenesis of pyelonephritis and renal scarring is not fully understood.8 Findings from one study9 showed that scars formed in 40 percent of refluxing kidneys and 43 percent of nonrefluxing kidneys. While some researchers emphasize the risk of renal scarring from recurrent UTI without reflux,10 others are just as adamant regarding the risk of scarring from reflux in the absence of infection.11 The fact that renal scarring develops in only a minority of patients with pyelonephritis and/or vesicoureteral reflux suggests that the development of renal scarring likely involves the interplay of several factors and cannot simply be attributed to the presence of infection or reflux alone (Figure 1).

Clinical Presentation
The clinical presentation of UTI is variable. In a child with so-called "asymptomatic" bacteriuria, only subtle clues, such as enuresis or squatting, may be present. Alternatively, a systemically ill neonate may be lethargic and hypotensive (Table 1). Although children are often managed on the basis of clinical symptoms and signs alone, these may be unreliable predictors of which patients are at risk for pyelonephritis and scarring.12,13 On the other hand, radiologic tests to confirm pyelonephritis or reflux can be expensive, time-consuming, invasive and undesirable to parents

The physical examination of a child with a possible UTI should exclude hypertension, an abdominal or flank mass, or a palpable bladder, neurologic deficits, abnormal genitalia and an abnormal urinary stream.1 This will help the clinician to find associated disorders.
The presence of irritative urinary symptoms in the absence of bacteria suggests a non-UTI cause such as vaginitis, urethritis, pinworms, or the use of bubble baths.1

Diagnosis
Maintaining a high index of suspicion for UTI in febrile children, particularly when an unexplained fever lasts two to three days, will lessen the number of missed UTIs. The most recent guideline issued by the American Academy of Pediatrics (AAP) for the evaluation of fever (39.0°C [102.2°F] or higher) of unknown origin suggests urinalysis in all cases and a urine culture in all boys younger than six months of age and all girls younger than two years of age.15
In infants, suprapubic aspiration or bladder catheterization and, in older children, a clean-voided midstream specimen are essential for diagnosis of UTI.1 Although convenient, use of adhesive perineal bags or wringing liquid from a wet diaper to collect urine is suboptimal, as bacteria from fecal contamination or urethral colonization may be misinterpreted as UTI. Although there is debate about the best way to screen female infants for UTI,16 many support criteria set by Dagan and colleagues.17 According to these criteria, a finding of more than 5 white blood cells per high-power field in centrifuged fresh urine is a satisfactory positive screening test.

Pyuria, proteinuria and hematuria may occur with or without UTI.1 Conversely, UTI can occur without pyuria.1 The determinations of nitrite concentrations and leukocyte esterase are not sensitive enough in children to indicate the need for urine culture.1 A properly obtained positive urine culture is essential for the diagnosis of UTI. Any number of colonies from a suprapubic bladder aspiration, more than 103 colonies from an intermittent ("in-and-out") catheterization, and more than 105 colonies from a midstream clean-catch urine collection indicate UTI.5
Most UTIs are caused by a single organism; the presence of two or more organisms usually suggests contamination. A urine culture is not mandatory in adolescent girls, particularly with a first episode. With recurrent episodes, episodes that fail therapy and in girls with pyuria without bacteriuria, a culture is recommended.

Special Issues
Recurrent UTI
Recurrent UTI is defined as two or more UTIs over a six-month period.7 It is useful to determine whether recurrence is caused by inadequate treatment of an unrecognized anatomic site of bacterial persistence (small infected calculus or unrecognized anatomic abnormality).14 As mentioned previously, recurrent UTI increases the risk of subsequent renal scarring.

Vesicoureteral Reflux
Vesicoureteral reflux is the abnormal backwash of urine into the ureter or kidney.18 The most common radiologic studies for the evaluation of reflux are the voiding cystourethrogram and the isotope cystogram. The isotope cystogram is more sensitive than the voiding cystourethrogram for detecting reflux, while only the voiding cystourethrogram provides enough anatomic detail to identify the severity of reflux and the presence of anatomic abnormalities.
Because the isotope cystogram exposes the patient to less radiation than the voiding cystourethrogram, it may be the study of choice for follow-up evaluations and may be used as the initial study in girls.18 In boys, however, initial work-up should include a voiding cystourethrogram to detect urethral abnormalities such as urethral diverticulum or posterior urethral valves. Grades I and II reflux can be treated with antimicrobial prophylaxis along with a strict voiding regimen19; however, urologic consultation should be considered in grades III to V reflux as the condition may merit surgical correction.5

Breakthrough UTI
Breakthrough UTI may be caused by a change in the resistance pattern of organisms colonizing the urethra, noncompliance, vesicoureteral reflux or voiding dysfunction. Recognizing and addressing these associated factors are essential in treating breakthrough UTI. A study in girls showed that treatment of voiding dysfunction combined with double antimicrobial prophylaxis was significantly successful in preventing breakthrough UTI.20

Voiding Dysfunction
Voiding dysfunction is a general term encompassing several patterns of detrusor instability and incomplete bladder emptying seen on urodynamic testing. It is often associated with daytime enuresis and constipation.20 Patients with otherwise unexplained recurrent UTI, especially in the setting of daytime enuresis or constipation, may merit urodynamic testing. Children with voiding dysfunction are at increased risk for the development of vesicoureteral reflux and UTI. Treatment of voiding dysfunction includes timed voiding, treatment of constipation, prophylactic antibiotics and, in some cases, use of anticholinergic medication (e.g., oxybutynin [Ditropan] or propantheline [Pro-Banthine]) or biofeedback.

Asymptomatic Bacteriuria
Controversy continues regarding the need for antibiotic treatment of asymptomatic bacteriuria.21-25 If recurrent bacteriuria is truly asymptomatic, no antimicrobial treatment may be the best option, as some studies have shown that asymptomatic children are at very low risk of renal scarring, and prophylactic treatment did not decrease the risk of UTI recurrence.14

Diagnostic Imaging
There is more controversy than consensus regarding the appropriateness of different diagnostic imaging modalities in the evaluation of UTI in children.26-28 The most commonly used imaging techniques are discussed in the following sections.

Ultrasonography
Although intravenous urography has been a time-honored examination in the initial radiologic evaluation of UTI in children,9 ultrasonography has largely replaced intravenous urography as the initial screening examination.8 Ultrasonography alone is not generally adequate for investigation of UTI in children, as it is unreliable in detecting vesicoureteral reflux, renal scarring or inflammatory changes.29 If reflux or morphologic abnormalities are identified, renal scintigraphy and voiding cystourethrography are recommended to further search for renal scarring or urinary tract abnormalities.

Intravenous Urography
Intravenous urography provides a precise anatomic image of the kidneys and can readily identify some urinary tract abnormalities (e.g., cysts, hydronephrosis).30 The major disadvantages of intravenous urography include decreased sensitivity compared with renal scintigraphy in the detection of both pyelonephritis and renal scarring.30 Higher dosage of radiation and risk of reaction to contrast medium are also reasons for concern. Given these disadvantages, intravenous urography appears to have little role in the work-up of UTI in children.

Renal Cortical Scintigraphy
Renal cortical scintigraphy has replaced intravenous urography as the standard technique for the detection of renal inflammation and scarring.8 Renal cortical scintigraphy with either technetium-99mlabeled glucoheptonate or dimercaptosuccinic acid (DMSA) are both highly sensitive and specific.8 DMSA scanning offers the advantages of earlier detection of acute inflammatory changes and permanent scars compared with ultrasound or intravenous urography. It is also useful in neonates and patients with poor renal function. Computed tomography (CT) is sensitive and specific for the detection of acute pyelonephritis, but no study is available that compares CT and scintigraphy.8 Furthermore, CT is more expensive than scintigraphy and exposes the patient to higher levels of radiation, and its use is not supported by evidence.

Voiding Cystourethrography
Because vesicoureteral reflux is a risk factor for reflux nephropathy and renal scars, early identification of this condition is warranted.4 Voiding cystourethrography should be delayed until after urinary infection is controlled, because vesicoureteral reflux may be the transient effect of infection. However, because of low sensitivity and specificity, and because voiding cystourethrography involves gonadal irradiation and catheterization, its use in diagnosing vesicoureteral reflux has been questioned.31

Isotope Cystogram
Although the isotope cystogram causes the same discomfort as bladder catheterization used in voiding cystourethrography, it has the advantage of an ionization radiation dose that is only 1 percent of that used for voiding cystourethrography,5 and its continuous monitoring is also more sensitive for identifying reflux than the intermittent flouroscopic monitoring of voiding cystourethrography.
Table 2 reviews the medical imaging techniques used in evaluating UTI in children.

Treatment
Therapeutic trials in children with UTI are rare and poorly controlled.32 Thus, controversy regarding dosage or length of therapy with antimicrobials continues. In patients who appear toxic, it is reasonable to initiate treatment with intravenous antibiotics and follow them closely for signs and symptoms of infection (fever, severe pain); these usually resolve in three to five days.33 Initial antibiotic therapy should be based on age, clinical severity, location of infection, presence of structural abnormalities, and allergy to certain antibiotics. Treatment generally begins with a broad-spectrum antibiotic, but it may need to be changed based on the results of urine culture and sensitivity testing.
Hospitalization is suggested for symptomatic young infants (less than three months of age) and all children with clinical evidence of acute severe pyelonephritis (high fever, toxic appearance, severe flank pain).33
The duration of outpatient treatment for patients with a less toxic appearance and uncomplicated UTI (no systemic signs of infection) is also controversial.1 Evidence is lacking for the use of short-course therapy in children with UTI.26 Although conventional therapy lasts seven to 10 days, a three- to seven-day trial of oral antibiotics has been suggested for uncomplicated infection of the lower urinary tract.32

Reasonable choices for initial inpatient and outpatient oral antibiotic therapy are shown in Table 3.24 Because of the possibility of bacterial resistance to a prophylactic agent used for long-term suppression, the treating antimicrobial agent for a breakthrough UTI should, ideally, be different from the prophylactic agent17 (Table 3).

Follow-up and Chemoprophylaxis
A urine culture should be obtained three to seven days after the completion of treatment to exclude relapse. Prophylaxis is recommended for all children younger than five years of age with vesicoureteral reflux (who are not surgical candidates) or other structural abnormalities and in children who have had three documented UTIs in one year.1 With careful monitoring for side effects, a prophylactic trial of a single nightly dose of nitrofurantoin (Furadantin, Macrodantin), 1 to 2 mg per kg per day, or trimethoprim-sulfamethoxazole (Bactrim, Septra), 2 mg per kg of trimethoprim per day, may be used for six months or more.8 Using low doses of antibiotics for prophylaxis has a theoretic advantage since this may minimize serum levels and subsequent enteric bacterial resistance while urinary concentration of the antibiotic remains high enough to maintain sterile urine.14

Prevention/Patient Education
A common-sense approach to prevention is advised by most authors.24,34 Good hygiene (including "front-to-back" wiping after urination in girls), avoidance or correction of constipation, and avoidance of bubble baths, chemical irritants and tight clothing might be recommended.
The role of circumcision in preventing UTI is controversial.25,35 The AAP states that "newborn circumcision has potential medical benefits and risks." When circumcision is being considered, the benefits and risks should be explained to the parents, and informed consent should be obtained.36

Final Comment
In light of the controversies and current literature, we propose our outline of management of UTI in children (Figures 2, 2a and 2b).

FIGURE 2 Algorithm for the management of urinary tract infection in children. See Figures 2a and 2b for treatment groups A and B. (UTI=urinary tract infection; VCUG=voiding cystourethrography)

For a primary care physician, it is imperative to maintain a high index of suspicion for UTI in children. By uncovering UTI and associated disorders, the goal of preventing renal infections, renal insufficiency, hypertension and end-stage renal disease can be realized.

In any child with systemic signs of illness, treatment with parenteral antibiotics should be initiated, and after clinical improvement, therapy
should be switched to oral antibiotics for 10 to 14 days. Diagnostic imaging with ultrasound and renal cortical scintigraphy should be considered to document the presence of pyelonephritis or renal scarring; voiding cystourethrography should be performed when the urine is sterile and the patient is clinically improved. Further management is dictated by the clinical course and findings on medical imaging (Figure 2a).

FIGURE 2A Algorithm for treatment group A.

FIGURE 2B Algorithm for treatment group B.

In all patients less than five years of age with no systemic signs and in boys over age five with no systemic signs, treatment with oral antibiotics should be carried out for 10 to 14 days. Afterward, diagnostic imaging with ultrasound and voiding cystourethrogram should be considered. Further management is dictated by findings on diagnostic imaging and clinical course (Figure 2b).
In girls over five years of age with no systemic signs, treatment with oral antibiotics should be carried out for seven to 10 days. Diagnostic imaging in these patients is not necessary with the first UTI but may be indicated in cases of recurrent UTI. Further management is outlined in Figure 2b.
The authors thank Leonardo M. Canessa, M.D., Jeanne P. Lemkau, Ph.D., Ahmed Hamidinia, M.D., and Juan Palomar, M.D., for reviewing the manuscript. The authors also thank Julie Mougey for assistance in the preparation of the manuscript.

The Authors
SYED M. AHMED, M.D., M.P.H., PH.D.,
is assistant professor in the family practice residency program at Wright State University School of Medicine/ Miami Valley Hospital, Dayton, Ohio. Dr. Ahmed is a graduate of Sir. Salimullah Medical College, Dhaka University, Dhaka, Bangladesh. He completed a residency and fellowship in family medicine at Baylor College of Medicine, Houston.
STEVEN K. SWEDLUND, M.D.,
is associate clinical professor in the Department of Family Practice at Wright State University School of Medicine and associate director of the Miami Valley Hospital Family Practice Residency. He earned a medical degree from Southern Illinois University School of Medicine, Springfield, and completed a residency in family medicine at St. Elizabeth Medical Center, Dayton.

Urinary Tract Infections in Children: Why They Occur and How to Prevent Them

STANLEY HELLERSTEIN, M.D.,
University of MissouriKansas City School of Medicine and Children's Mercy Hospital, Kansas City, Missouri

Urinary tract infections (UTIs) usually occur as a consequence of colonization of the periurethral area by a virulent organism that subsequently gains access to the bladder. During the first few months of life, uncircumcised male infants are at increased risk for UTIs, but thereafter UTIs predominate in females. An important risk factor for UTIs in girls is antibiotic therapy, which disrupts the normal periurethral flora and fosters the growth of uropathogenic bacteria. Another risk factor is voiding dysfunction. Currently, the most effective intervention for preventing recurrent UTIs in children is the identification and treatment of voiding dysfunction. Imaging evaluation of the urinary tract following a UTI should be individualized, based on the child's clinical presentation and on clinical judgment. Both bladder and upper urinary tract imaging with ultrasonography and a voiding cystourethrogram should be obtained in an infant or child with acute pyelonephritis. Imaging studies may not be required, however, in older children with cystitis who respond promptly to treatment.
Urinary tract infections (UTIs) are common in children. The treatment goals are to eliminate the infection and prevent kidney damage. The usual approach in children is to first treat the infection and then obtain imaging studies of the urinary tract. This article focuses on why children have UTIs and what can be done to prevent them.

Factors That Predispose Children to UTIs
Circumcision
Uncircumcised male infants appear to be at increased risk of UTIs in the first three months of life. In a study of 100 otherwise healthy infants ranging in age from five days to eight months and admitted to the hospital because of a first known UTI,1 most of the UTIs in infants younger than three months of age were in males, but female infants predominated thereafter. The fact that 95 percent of the male infants in the study were not circumcised led to speculation that the uncircumcised male has an increased susceptibility to UTI--at least early in life.
This issue was examined in a retrospective study at Tripler Army Medical Center.2 The study showed that uncircumcised boys had a 4.1 percent incidence of UTI during their first year of life, while girls had an incidence of 0.5 percent and circumcised males an incidence of 0.2 percent. Subsequently, a large retrospective study of infants cared for in U.S. Army hospitals supported the theory that circumcision protects against UTIs in young male infants. The periurethral area was found to be more frequently and more heavily colonized with uropathogens, especially Escherichia coli, in uncircumcised infants than in circumcised infants.3
Winberg and associates4 offer an explanation for the high incidence of UTIs in uncircumcised male infants in an intriguing article, "The Prepuce: A Mistake of Nature?" They suggest that one unphysiologic intervention--circumcision--serves to counterbalance the effect of another unphysiologic state of affairs--exposure of the infant to the microbiologic environment of the maternity unit. In a natural biologic setting, with no perineal shaving or cleansing, mothers often defecate when giving birth in a squatting or kneeling position. Because of this, the infant is colonized at birth with the mother's aerobic and anaerobic bacteria. The infant receives specific protection against infection from these bacteria through immunoglobulins transferred from the mother during gestation and after delivery in the mother's breast milk.
In contrast, babies born and cared for in a hospital are likely to be colonized by strains acquired from the external environment, against which their mothers may have no immunity. Such infants have little protection against infection from hospital-acquired strains of E. coli that colonize the gastrointestinal tract, the perineum and the periurethral area in females and preputial area in uncircumcised males. Colonization of the prepuce by these potentially dangerous bacteria places the uncircumcised male at high risk for a UTI. Circumcision diminishes that risk.

Changes in the Periurethral Flora
It is not only in the male that the character of the periurethral flora is a key factor in the occurrence of UTIs. After the first few months of life, UTIs occur far more frequently in girls than in boys, presumably because of the shorter length of the female urethra. Following birth, heavy periurethral colonization with aerobic bacteria normally becomes established in both sexes.5 Colonization with E. coli and enterococci diminishes during the first year and normally becomes light after five years of age.
Adult women prone to recurrent UTIs have colonization of the periurethral area with the specific microbe that will cause the next infection.6 Similar findings were demonstrated in studies of UTIs in school-aged girls.7,8 The periurethral area is colonized by both anaerobic and aerobic bacteria from the gastrointestinal tract, which serve as part of a normal defense barrier against pathogenic microorganisms.

Two studies indicate that breast feeding protects against UTIs, both during the time the infant is receiving breast milk and for a period after breast feeding is discontinued, presumably by promoting a stable intestinal flora with fewer potentially pathogenic strains.9,10 Disturbance of the normal periurethral flora fosters colonization by potential uropathogens. Experimental and clinical studies show that resistance to colonization by uropathogens can be broken down by administration of amoxicillin or a first-generation cephalosporin (Cephadroxil).11 Of special interest is a study of girls with respiratory infections treated with trimethoprim-sulfamethoxazole; the study showed that this antimicrobial agent did not disturb the normal flora.12

Voiding Dysfunction
Voiding dysfunction is characterized by some or all of the following: urgency, frequency, dysuria, hesitancy, dribbling of urine and overt incontinence. Symptoms of voiding dysfunction may be secondary to a UTI or to local irritants such as pinworm infestation or bubble bath, or hypercalciuria.
In the anatomically and neurologically normal child, voiding dysfunction is usually caused by persistence of an unstable urinary bladder, an important contributor to recurrent UTIs. An unstable urinary bladder is a common functional disorder and usually has been present since daytime urinary control was first developing in the child. The outstanding characteristic is persistent urinary urgency.
Recognition and management of voiding dysfunction is the area in which the physician can be most effective in the prevention of recurrent UTIs. A girl with voiding dysfunction is at increased risk for recurrent UTIs because of reflux of urine laden with bacteria from the distal urethra into the bladder.13 Studies have demonstrated that reflux of contrast material from the distal urethra into the bladder occurs when continence is maintained by contraction or compression of the bladder outlet rather than by the normal neurogenic inhibition of the detrusor contraction. Normally, the distal urethra is not sterile but has a flora similar to that of the periurethral area. When urinary leakage is prevented by compression of the urethral sphincter during an uninhibited contraction, the flat bladder base becomes funnel shaped and the posterior urethra is filled with urine. Shortly thereafter, when the contraction subsides, bacteria-laden urine from the urethra may reflux back into the bladder. Reflux of contaminated urine into the bladder, which itself may have an increased susceptibility to infection because of ischemia resulting from uninhibited detrusor contraction, is the explanation for recurrent UTIs in many children.
A relationship between constipation and UTIs is well known.14 It has been shown that constipation per se, with a dilated rectum, causes the same pattern of voiding dysfunction as that encountered in children with persistence of an unstable bladder. Effective treatment of the constipation results in normalization of bladder function and cessation of UTIs.15

Prevention of UTIs
The first step in the prevention of UTIs in the neurologically intact child with an unobstructed urinary tract is to ask, "Why does this child have a UTI at this time?" A detailed voiding and defecation history should be obtained. Recent treatment of an upper respiratory infection with amoxicillin or a cephalosporin may indicate the need to try to avoid prescribing these agents for the child in the future. However, if amoxicillin or a cephalosporin is required for treatment of an upper respiratory infection, it is important not to discontinue therapy with nitrofurantoin (Macrodantin) or trimethoprim-sulfamethoxazole (Bactrim, Septra) in the child who is receiving suppressive antimicrobial therapy to prevent recurrent UTIs. We frequently encounter a child with recurrence of a UTI when this happens, possibly because of the effect on the periurethral flora or because of the high incidence of amoxicillin-resistant E. coli.
Physical examination should include careful inspection of the lumbosacral area for signs of underlying dysraphism (pilonidal sinus, tuft of hair, etc.). A rectal examination should be performed to detect a large fecal reservoir, even if there is no history of constipation.
Voiding dysfunction is treated with the use of a voiding retraining program that emphasizes good voiding technique, usually following a timed voiding schedule. In many instances a pharmacologic agent such as oxybutynin (Ditropan), propantheline (ProBanthine) or hyoscyamine sulfate (Levsin) is helpful. The goal is to eliminate the episodes of urinary urgency, during which there may be reflux of bacteria-laden urine from the distal urethra into the urinary bladder. Anticholinergic agents not only alter bladder function but also suppress intestinal motility, so attention to constipation must be ongoing.

UTI Prevention Myths
Some forms of intervention to prevent recurrent UTIs in children, mainly young girls, appear to be based more on myth than on substance. Perineal hygiene is regularly emphasized. For aesthetic reasons, it seems appropriate to instruct girls to wipe from front to back, but no data indicate that this practice prevents vaginal and vulval colonization with Enterobacteriaceae.16 According to Kunin,17 the commonly held view that UTIs in women are caused by fecal contamination of the periuretheral zone is unproved. If UTIs were caused by fecal contamination, one would expect to find multiple strains of E. coli in the vaginal introitus and periurethral area of these women. However, women prone to recurrent UTIs are colonized by a single pathogen, while healthy adult females have few or no E. coli in these areas.18 If fecal soiling were an important factor in the pathogenesis of UTIs, female infants would have a very high incidence of UTIs prior to achieving bowel control.
Some girls prone to recurrent UTIs are told that they should give up tub-bathing and swimming. These suggestions are based on the concept that UTIs in girls are a result of vulvourethral reflux of tub or pool water into the bladder. However, a careful study of this possibility, using inulin as a tracer in bath water, failed to show inulin in bladder urine.19 There appears to be no basis for the suggestion that girls eliminate bathing or swimming in order to prevent UTIs.
A significant segment of the U.S. population believes that cranberry-derived beverages prevent or cure UTIs. The presumed antibacterial effects of cranberry juice are controversial, attributed by some to urinary acidification and by others to a direct bacteriostatic effect of hippuric acid on E. coli.20 Clinical studies have not been convincing. At this juncture, it seems reasonable not to discourage children who are prone to UTIs, and who like and tolerate cranberry-derived beverages, from ingesting them, while emphasizing that these beverages cannot be viewed as a substitute for an antibiotic in the treatment of a UTI or as a substitute for other measures to prevent reinfection.

Diagnosis of UTIs
The specimen for urinalysis and culture should be obtained by catheter or suprapubic aspiration in the infant or child unable to void on request. Suprapubic aspiration is the method of choice in the uncircumcised male. A midstream clean-catch specimen may be obtained from the child with urinary control. A bagged specimen of urine that shows no growth or fewer than 10,000 colony-forming units (CFU) per mL is evidence of the absence of a UTI. If the child who has not yet achieved urinary control has symptoms that mandate immediate treatment, and analysis of the urine specimen obtained by bag shows pyuria, or tests for positive nitrite or bacteriuria, a urine sample should be obtained by suprapubic aspiration or catheter before starting antibiotic therapy because of the high incidence of false-positive bagged urine cultures.
Treatment of acute pyelonephritis or cystitis may be initiated based on the urinalysis findings. However, the diagnosis of a UTI is not documented by urinalysis, and imaging studies of the urinary tract should not be obtained until the diagnosis of UTI is confirmed by a positive urine culture.

Cystitis
Infants and young children with cystitis who have not yet achieved urine control often present with low-grade fever (usually less than 38°C [100.4°F]), discomfort or crying with urination, mild behavior change and, at times, foul-smelling urine. Older children with cystitis usually present with any or all of the following: urinary urgency, frequency, hesitancy, dysuria and, at times, incontinence. No fever or only a low-grade fever is present. Some children have suprapubic pain or tenderness. A tentative diagnosis of cystitis may be made if there are urinary findings on the dipstick examination or microscopic evidence suggestive of a UTI.

Acute Pyelonephritis
Acute pyelonephritis may be diagnosed in the infant or young child with fever (a rectal or tympanic membranederived temperature of 38°C [100.4°F] or greater) unexplained by the history or physical examination and urinary findings suggestive of a UTI--i.e., positive nitrite and/or leukocyte esterase and/or bacteria in the centrifuged urinary sediment. A good rule is that urine should be evaluated for the presence of infection in the infant or young child who has an unexplained fever for as long as three days. Acute pyelonephritis may be diagnosed in the older child with fever, systemic symptoms, costovertebral angle or flank tenderness and urinary findings suggestive of a UTI.

Asymptomatic Bacteriuria
Children, usually school-aged girls, with significant bacteriuria in the absence of any symptoms do not require further evaluation of the urinary tract or treatment. An exception, of course, are children asymptomatic at the time a urine specimen is obtained who have a history of vesicoureteral reflux or recurrent UTIs.

Imaging Evaluation Following a UTI
An algorithm for the management of children with the presumptive diagnosis of a UTI is presented in Figure 1. The literature describing various protocols for the imaging evaluation of the urinary tract following a UTI is extensive. Unfortunately, no prospective studies with long-term outcome data are available.21 Some experts recommend that all children with a UTI be investigated with urinary tract ultrasonography. With regard to children younger than one year, two years or five years, some experts recommend urinary tract ultrasonography and cystography.22-26 Some would obtain only cortical imaging (DMSA or glucoheptonate nuclear scans) or cystography if these studies are normal. In addition, there are those who suggest that no imaging is needed in the child with cystitis who responds promptly to treatment.27-29

FIGURE 1 Algorithm for the management of children with a presumptive diagnosis of UTI.

UTI=urinary tract infection; IV=intravenous; US=ultrasound examination. * --In children with a UTI, a cystogram may be obtained when the urine is free of bacteria and pus cells and the voiding pattern has reverted to the pattern that was present before the UTI. † --Suppressive antibiotic therapy is recommended for 6 months in all children who have had acute pyelonephritis but may be continued longer in those with vesicoureteral reflux.

Suggested Imaging Evaluation of a Child with a UTI
Children who are to have a cystogram as part of the imaging evaluation for a UTI should receive therapeutic or suppressive doses of antibiotic until after the bladder imaging study. The following recommendations for the imaging evaluation of children following a UTI are based on a review of the literature, experience and reason.
" In the neonate with urosepsis and in the infant, child or adolescent with a clinical diagnosis of acute pyelonephritis documented by urine culture:
1. Urinary tract ultrasound examination to identify an obstructive abnormality.
2. A contrast voiding cystourethrogram to evaluate the urinary bladder and urethra and detect vesicoureteral reflux.
Management of the acute illness is based on the clinical diagnosis of acute pyelonephritis. A significant obstructive abnormality will be disclosed by ultrasound examination. If vesicoureteral reflux is present, long-term suppressive antibiotic therapy may be indicated.30 Some clinicians recommend six months of suppressive antibiotic therapy for children who have pyelonephritis in the absence of vesicoureteral reflux (nonrefluxing pyelonephritis). This is, however, an empiric recommendation related to the relatively high recurrence rate of UTIs in girls in the first months following a primary infection.
" In the infant or child from about one to five years of age who has had one or several episodes of cystitis that responded promptly to therapy:
1. Imaging evaluation after a first episode of cystitis if the child has a history of unexplained fever or there is a family history of vesicoureteral reflux.
2. Urinary tract ultrasonography to identify structural abnormalities.
3. Nuclear cystogram to detect vesicoureteral reflux in girls who have a normal voiding pattern when they are uninfected.
4. Contrast voiding cystourethrogram in all boys and girls who have an abnormal voiding pattern. The study should be done when the child is free of infection.
" In the child older than five years after one or several episodes of cystitis:
1. Urinary tract ultrasonography in all children except a pubescent girl who may have become sexually active. (If a pubescent girl has several episodes of clinical cystitis within a year, a urinary tract ultrasound examination should be obtained.) No further studies are required if the ultrasound examination is normal.
2. If the ultrasound examination is abnormal, contrast cystourethrogram should be performed in all children with one or several episodes of cystitis.
The literature review for the manuscript was done in preparation for the Stanley Levine, M.D., Memorial Lecture, presented on April 4, 1997, at the Schneider Children's Hospital, Long Island, N.Y. The author thanks Carol Burns for secretarial support in the preparation of both the lecture and the manuscript.

The Author

STANLEY HELLERSTEIN, M.D.,
is professor of pediatrics at the University of Missouri Kansas City School of Medicine and a member of the Section of Pediatric Nephrology at Children's Mercy Hospital, also in Kansas City, Mo. He graduated from the University of Colorado School of Medicine, Denver, and completed an internship and pediatric residency at Indiana University Medical Center, Indianapolis. After a two-year fellowship in fluid and electrolyte metabolism at the University of Kansas School of Medicine, Kansas City, Kan., and Children's Mercy Hospital, Dr. Hellerstein spent six years in private practice. He then returned to Children's Mercy Hospital, where he founded the Section of Pediatric Nephrology. Over the past 25 years, the evaluation and management of children with urinary tract infections has been the focus of much of his clinical, research and scholarly efforts.