Prevalence and Etiology

Urinary tract infections (UTIs) occur in 1-3% of girls and 1% of boys. In girls, the first UTI usually occurs by the age of 5 yr, with peaks during infancy and toilet training. In boys, most UTIs occur during the 1st yr of life; UTIs are much more common in uncircumcised boys, especially in the 1st year of life. The prevalence of UTIs varies with age. During the 1st yr of life, the male : female ratio is 2.8-5.4 : 1. Beyond 1-2 yr, there is a female preponderance, with a male : female ratio of 1 : 10.

UTIs are caused mainly by colonic bacteria. In girls, 75-90% of all infections are caused by Escherichia coli (Chapter 192), followed by Klebsiella spp and Proteus spp. Some series report that in boys >1 yr of age, Proteus is as common a cause as E. coli; others report a preponderance of gram-positive organisms in boys. Staphylococcus saprophyticus and enterococcus are pathogens in both sexes. Adenovirus and other viral infections also can occur, especially as a cause of cystitis.

Historically, UTIs have been considered a risk factor for the development of renal insufficiency or end-stage renal disease in children. Some researchers have questioned the importance of UTI as a risk factor, because only 2% of children with renal insufficiency report a history of UTI. This paradox may be secondary to better recognition of the risks of UTI and prompt diagnosis and therapy. Furthermore, many children receive antibiotics for fever without a focus (such as treating a questionable otitis media) resulting in a partially treated UTI.

Clinical Manifestations and Classification

The 3 basic forms of UTI are pyelonephritis, cystitis, and asymptomatic bacteriuria. Focal pyelonephritis (nephronia) and renal abscesses are less common.

Clinical Pyelonephritis

Clinical pyelonephritis is characterized by any or all of the following: abdominal, back, or flank pain; fever; malaise; nausea; vomiting; and, occasionally, diarrhea. Fever may be the only manifestation. Newborns can show nonspecific symptoms such as poor feeding, irritability, jaundice, and weight loss. Pyelonephritis is the most common serious bacterial infection in infants <24 mo of age who have fever without an obvious focus (Chapter 170). These symptoms are an indication that there is bacterial involvement of the upper urinary tract. Involvement of the renal parenchyma is termed acute pyelonephritis, whereas if there is no parenchymal involvement, the condition may be termed pyelitis. Acute pyelonephritis can result in renal injury, termed pyelonephritic scarring.

Acute lobar nephronia (acute lobar nephritis) is a renal mass caused by acute focal infection without liquefaction. It may be an early stage in the development of a renal abscess. Manifestations are identical to pyelonephritis; renal imaging demonstrates the abnormality (Fig. 532-1). Renal abscess can occur following a pyelonephritic infection due to the usual uropathogens or may be secondary to a primary bacteremia (S. aureus). Perinephric abscess (see Fig. 532-4) can occur secondary to contiguous infection in the perirenal area (e.g., vertebral osteomyelitis, psoas abscess) or pyelonephritis that dissects to the renal capsule.

Figure 532-1 Characteristic precontrast (A) and contrast-enhanced (B) CT scans for an 8 mo old patient who had acute lobar nephronia and presented with severe bilateral nephromegaly but without a focal mass sonographically. No attenuation area is seen in the kidney before enhancement.

(From Cheng CH, Tsau YK, Lin TY: Effective duration of antimicrobial therapy for the treatment of acute lobar nephronia, Pediatrics 117:e84–e89, 2006.)

Xanthogranulomatous pyelonephritis is a rare type of renal infection characterized by granulomatous inflammation with giant cells and foamy histiocytes. It can manifest clinically as a renal mass or an acute or chronic infection. Renal calculi, obstruction, and infection with Proteus spp or E. coli contribute to the development of this lesion, which usually requires total or partial nephrectomy.

Pathogenesis and Pathology

Most UTIs are ascending infections. The bacteria arise from the fecal flora, colonize the perineum, and enter the bladder via the urethra. In uncircumcised boys, the bacterial pathogens arise from the flora beneath the prepuce. In some cases, the bacteria causing cystitis ascend to the kidney to cause pyelonephritis. Rarely, renal infection occurs by hematogenous spread, as in endocarditis or in some neonates.

If bacteria ascend from the bladder to the kidney, acute pyelonephritis can occur. Normally the simple and compound papillae in the kidney have an antireflux mechanism that prevents urine in the renal pelvis from entering the collecting tubules. However, some compound papillae, typically in the upper and lower poles of the kidney, allow intrarenal reflux. Infected urine then stimulates an immunologic and inflammatory response. The result can cause renal injury and scarring (Figs. 532-2 and 532-3). Children of any age with a febrile UTI can have acute pyelonephritis and subsequent renal scarring, but the risk is highest in those <2 years of age.

Figure 532-2 Scarred kidney from recurrent pyelonephritis.

Figure 532-3 CT scan showing an area of parenchymal thinning corresponding to an underlying calyx, characteristic of pyelonephritic scarring or reflux nephropathy.

Host risk factors for UTI are listed in Table 532-1. Vesicoureteral reflux is discussed in Chapter 533. If there is grade III, IV, or V vesicoureteral reflux and a febrile UTI, 90% have evidence of acute pyelonephritis on renal scintigraphy or other imaging studies. In girls, UTIs often occur at the onset of toilet training because of voiding dysfunction that occurs at that age. The child is trying to retain urine to stay dry, yet the bladder may have uninhibited contractions forcing urine out. The result may be high-pressure, turbulent urine flow or incomplete bladder emptying, both of which increase the likelihood of bacteriuria. Voiding dysfunction can occur in the toilet-trained child who voids infrequently. Similar problems can arise in school-age children who refuse to use the school bathroom. Obstructive uropathy resulting in hydronephrosis increases the risk of UTI because of urinary stasis. Urethral catheterization for urine output monitoring or during a voiding cystourethrogram or nonsterile catheterization can infect the bladder with a pathogen. Constipation with fecal impaction can increase the risk of UTI because it can cause voiding dysfunction.

The pathogenesis of UTI is based in part on the presence of bacterial pili or fimbriae on the bacterial surface. There are two types of fimbriae, type I and type II. Type I fimbriae are found on most strains of E. coli. Because attachment to target cells can be blocked by D-mannose, these fimbriae are referred to as mannose-sensitive. They have no role in pyelonephritis. The attachment of type II fimbriae is not inhibited by mannose, and these are known as mannose-resistant. These fimbriae are expressed by only certain strains of E. coli. The receptor for type II fimbriae is a glycosphingolipid that is present on both the uroepithelial cell membrane and red blood cells. The Gal 1-4 Gal oligosaccharide fraction is the specific receptor. Because these fimbriae can agglutinate by P blood group erythrocytes, they are known as P fimbriae. Bacteria with P fimbriae are more likely to cause pyelonephritis. Between 76-94% of pyelonephritogenic strains of E. coli have P fimbriae, compared with 19-23% of cystitis strains.

Other host factors for UTI include anatomic abnormalities precluding normal micturition, such as a labial adhesion. This lesion acts as a barrier and causes vaginal voiding. A neuropathic bladder can predispose to UTIs if there is incomplete bladder emptying and/or detrusor-sphincter dyssynergia. Sexual activity is associated with UTIs in girls, in part because of incomplete bladder emptying. From 4-7% of pregnant women have asymptomatic bacteriuria, which can develop into a symptomatic UTI. The incidence of UTI in infants who are breast-fed is lower than in those fed with formula.

Diagnosis

UTI may be suspected based on symptoms or findings on urinalysis, or both; a urine culture is necessary for confirmation and appropriate therapy. There are several ways to obtain a urine sample; some are more accurate than others. In toilet-trained children, a midstream urine sample usually is satisfactory; the introitus should be cleaned before obtaining the specimen. In uncircumcised boys, the prepuce must be retracted; if the prepuce is not retractable, a voided sample may be unreliable and contaminated with skin flora. In children who are not toilet trained, a catheterized urine sample should be obtained. Alternatively, the application of an adhesive, sealed, sterile collection bag after disinfection of the skin of the genitals can be useful only if the culture is negative or if a single uropathogen is identified. However, a positive culture can result from skin contamination, particularly in girls and uncircumcised boys. If treatment is planned immediately after obtaining the urine culture, a bagged specimen should not be the method because of a high rate of contamination often with mixed organisms. A suprapubic aspirate generally is unnecessary.

Pyuria (leukocytes in the urine) suggests infection, but infection can occur in the absence of pyuria; this finding is more confirmatory than diagnostic. Conversely, pyuria can be present without UTI.

Sterile pyuria (positive leukocytes, negative culture) occurs in partially treated bacterial UTIs, viral infections, renal tuberculosis, renal abscess, UTI in the presence of urinary obstruction, urethritis due to a sexually transmitted infection (STI) (Chapter 114), inflammation near the ureter or bladder (appendicitis, Crohn disease), and interstitial nephritis (eosinophils). Nitrites and leukocyte esterase usually are positive in infected urine. Microscopic hematuria is common in acute cystitis, but microhematuria alone does not suggest UTI. White blood cell casts in the urinary sediment suggest renal involvement, but in practice these are rarely seen. If the child is asymptomatic and the urinalysis result is normal, it is unlikely that there is a UTI. However, if the child is symptomatic, a UTI is possible, even if the urinalysis result is negative.

Prompt plating of the urine sample for culture is important, because if the urine sits at room temperature for more than 60 min, overgrowth of a minor contaminant can suggest a UTI when the urine might not be infected. Refrigeration is a reliable method of storing the urine until it can be cultured.

If the culture shows >100,000 colonies of a single pathogen, or if there are 10,000 colonies and the child is symptomatic, the child is considered to have a UTI. In a bag sample, if the urinalysis result is positive, the patient is symptomatic, and there is a single organism cultured with a colony count >100,000, there is a presumed UTI. If any of these criteria are not met, confirmation of infection with a catheterized sample is recommended.

With acute renal infection, leukocytosis, neutrophilia, and elevated serum erythrocyte sedimentation rate and C-reactive protein are common. The latter 2 are nonspecific markers of bacterial infection, and their elevation does not prove that the child has acute pyelonephritis. With a renal abscess, the white blood cell count is markedly elevated to >20,000-25,000/mm³. Because sepsis is common in pyelonephritis, particularly in infants and in any child with obstructive uropathy, blood cultures should be considered before starting antibiotics if possible.

Treatment

Acute cystitis should be treated promptly to prevent possible progression to pyelonephritis. If the symptoms are severe, presumptive treatment is started pending results of the culture. If the symptoms are mild or the diagnosis is doubtful, treatment can be delayed until the results of culture are known, and the culture can be repeated if the results are uncertain. If treatment is initiated before the results of a culture and sensitivities are available, a 3- to 5-day course of therapy with trimethoprim-sulfamethoxazole (TMP-SMX) or trimethoprim is effective against most strains of E. coli. Nitrofurantoin (5-7 mg/kg/24 hr in 3-4 divided doses) also is effective and has the advantage of being active against Klebsiella and Enterobacter organisms. Amoxicillin (50 mg/kg/24 hr) also is effective as initial treatment but has no clear advantages over sulfonamides or nitrofurantoin.

In acute febrile infections suggesting pyelonephritis, a 10- to 14-day course of broad-spectrum antibiotics capable of reaching significant tissue levels is preferable. Children who are dehydrated, are vomiting, are unable to drink fluids, are ≤1mo of age, or in whom urosepsis is a possibility should be admitted to the hospital for IV rehydration and IV antibiotic therapy. Parenteral treatment with ceftriaxone (50-75 mg/kg/24 hr, not to exceed 2 g) or cefotaxime (100 mg/kg/24 hr), or ampicillin (100 mg/kg/24 hr) with an aminoglycoside such as gentamicin (3-5 mg/kg/24 hr in 1-3 divided doses) is preferable. The potential ototoxicity and nephrotoxicity of aminoglycosides should be considered, and serum creatinine and trough gentamicin levels must be obtained before initiating treatment, as well as daily thereafter as long as treatment continues. Treatment with aminoglycosides is particularly effective against Pseudomonas spp, and alkalinization of urine with sodium bicarbonate increases its effectiveness in the urinary tract.

Oral 3rd-generation cephalosporins such as cefixime are as effective as parenteral ceftriaxone against a variety of gram-negative organisms other than Pseudomonas, and these medications are considered by some authorities to be the treatment of choice for oral outpatient therapy. Nitrofurantoin should not be used routinely in children with a febrile UTI because it does not achieve significant renal tissue levels. The oral fluoroquinolone ciprofloxacin is an alternative agent for resistant microorganisms, particularly Pseudomonas, in patients >17 yr. It also has been used on occasion for short-course therapy in younger children with Pseudomonas UTI. However, the clinical use of fluoroquinolones in children should be restricted because of potential cartilage damage. In some children with a febrile UTI, intramuscular injection of a loading dose of ceftriaxone followed by oral therapy with a 3rd-generation cephalosporin is effective. A urine culture 1 wk after the termination of treatment of a UTI ensures that the urine is sterile but is not routinely needed. A urine culture during treatment almost invariably is negative.

Children with a renal or perirenal abscess or with infection in obstructed urinary tracts can require surgical or percutaneous drainage in addition to antibiotic therapy and other supportive measures (Fig. 532-4). Small abscesses may initially be treated without drainage.

Figure 532-4 A, Renal sonogram, 19 mo old girl with perirenal abscess secondary to methicillin-resistant Staphylococcus aureus. B, CT scan demonstrates extensive perinephric and focal intrarenal abscess. Patient underwent incision and drainage.

In a child with recurrent UTIs, identification of predisposing factors is beneficial. Many school-aged girls have voiding dysfunction (Chapter 537); treatment of this condition often reduces the likelihood of recurrent UTI. Some children with UTIs void infrequently, and many also have severe constipation (Chapter 298). Counseling of parents and patients to try to establish more normal patterns of voiding and defecation is most important in controlling recurrences. Prophylaxis against reinfection, using TMP-SMX, trimethoprim, or nitrofurantoin at 30% of the normal therapeutic dose once a day, is one approach to this problem. Prophylaxis with amoxicillin or cephalexin can also be effective, but the risk of breakthrough UTI may be higher because bacterial resistance may be induced. There is controversy about prophylaxis against recurrent UTIs in children with low-grade or no reflux because resistant organisms can develop, and the incidence of recurrent infection might not consistently be reduced. Other more high risk conditions for recurrent UTIs that might need long-term prophylaxis include neurogenic bladder, urinary tract stasis and obstruction, reflux, and calculi. There is interest in probiotic therapy, which replaces pathologic urogenital flora, and cranberry juice, which prevents bacterial adhesion and biofilm formation, but these agents have not proved beneficial in preventing UTI in children.

The main consequences of chronic renal damage caused by pyelonephritis are arterial hypertension and end-stage renal insufficiency; when they are found they should be treated appropriately (Chapters 439 and 529).

Imaging Studies

The goal of imaging studies in children with a UTI is to identify anatomic abnormalities that predispose to infection, determine whether there is active renal involvement, and to assess whether renal function is normal or at risk.

Acute pyelonephritis, typically characterized by fever, malaise, abdominal or flank pain, and occasionally nausea and vomiting, is a significant risk factor for renal injury and scarring. Acute pyelonephritis may be imaged with a technetium-labeled dimercaptosuccinic acid (DMSA) renal scan. Typically, involved areas of the kidney are photopenic and the kidney is enlarged. Of children with a febrile UTI, approximately 50% have a positive DMSA scan. Of those with a positive scan, approximately 50% develop renal scarring in the areas of acute pyelonephritis, and in the remainder with acutely positive scans, the renal appearance will normalize. In children with dilating grades of reflux (III, IV, V), 80-90% with a febrile UTI have a DMSA scan consistent with acute pyelonephritis. Children with grades I and II reflux and those without reflux can also develop acute pyelonephritis. In longitudinal studies of children with grades I and II reflux and acute pyelonephritis, the reflux usually resolves. If the DMSA scan is normal during a febrile UTI, no scarring will result from that particular infection. CT is another diagnostic tool that can image acute pyelonephritis, but clinical experience with DMSA is much greater, and CT scans have more radiation.

In children with their 1st episode of clinical pyelonephritis—those with a febrile UTI, or, in infants, those with systemic illness—and a positive urine culture, irrespective of temperature, a sonogram of kidneys and bladder should be performed to assess kidney size, detect hydronephrosis and ureteral dilation, identify the duplicated urinary tract, and evaluate bladder anatomy. Next, a DMSA scan is performed to identify whether the child has acute pyelonephritis (Fig. 532-5). If the DMSA scan is positive and shows either acute pyelonephritis or renal scarring, a voiding cystourethrogram (VCUG) is performed (Fig. 532-6). If reflux is identified, treatment is based on the perceived long-term risk of the reflux to the child (Chapter 533). One limitation to this approach is that many hospitals caring for children with a febrile UTI might not have facilities for performing a DMSA scan in children. In these cases, a renal sonogram should be performed, and then the clinician needs to decide on whether to send the child to a facility with DMSA capability or instead do a VCUG.

Figure 532-5 Dimercaptosuccinic acid renal scan showing bilateral photopenic areas indicating acute pyelonephritis and renal scarring. LPO, left posterior oblique; RPO, right posterior oblique.

Figure 532-6 Intrarenal reflux. Voiding cystourethrogram in an infant boy with a past history of a urinary tract infection. Note the right vesicoureteral reflux with ureteral dilatation, with opacification of the renal parenchyma representing intrarenal reflux.

In some centers, the VCUG is delayed for 2-6 wk to allow inflammation in the bladder to resolve; however, the incidence of reflux is identical, regardless of whether the VCUG is obtained acutely at the time of treatment of the UTI or after 6 wk. Obtaining the VCUG before the child is discharged from the hospital is appropriate and ensures that the evaluation is complete. If available, a radionuclide VCUG rather than a contrast VCUG can be used in girls; this technique causes less radiation exposure to the gonads than does the contrast study. However, the radioisotope VCUG does not provide anatomic definition of the bladder, allow precise grading of reflux, demonstrate a paraureteral diverticulum, or show whether reflux is occurring into a duplicated collecting system or an ectopic ureter. In boys, VCUG definition of the urethra is important to detect posterior urethral values (Chapter 534).

In children with a second febrile UTI who previously had a negative upper tract evaluation, a VCUG is indicated, because low-grade reflux predisposes to clinical pyelonephritis.

In children with ≥1 infection of the lower urinary tract (dysuria, urgency, frequency, suprapubic pain), imaging is usually unnecessary. Instead, assessment and treatment of bladder and bowel dysfunction is important. If there are numerous lower urinary tract infections, then a renal sonogram is appropriate, but a VCUG rarely adds useful information.

Alternative Recommendations for UTI

In 2007, the NICE (National Institute for Health and Clinical Excellence, UK) guidelines for diagnosis, management, and imaging after UTI were released. These recommendations divide children into those <6 mo, 6 mo to 3 yr, and >3 yr of age. The clinical categories are separated into those that respond to treatment within 48 hours, recurrent UTI, and atypical UTI (sepsis, non–E. coli UTI, suprapubic mass, elevated serum creatinine, hypertension). The recommendations include upper tract imaging with a renal sonogram and DMSA scan for all <6 mo with a UTI and all children <3 yr with an atypical or recurrent UTI. For children >3 yr, a DMSA scan is recommended only for recurrent UTI. A VCUG is recommended only in children <6 mo. These recommendations are highly controversial because the methodology was not based on evidence but on expert opinion. In addition, there was no retrospective or prospective assessment of the potential of this approach to identify significant uropathology. Coulthard and Tse have performed independent assessments of these recommendations and has found that a significant number of children with uropathology would not have been identified under these guidelines.

In 1999, the American Academy of Pediatrics released guidelines for management of children 2 m to 2 yr with a febrile UTI. This guideline recommended a renal sonogram and VCUG or radionuclide cystogram; at this time, these recommendations are being rewritten.