Urinary Tract Infections

Urinary tract infections (UTIs) are thought to play a role in renal scarring and the development of chronic kidney disease. As the number of UTI episodes increase, the overall risk for renal scarring greatly increases (from 5% after the first episode to 60% after the fifth episode). In a recent study, the incidence of renal scarring in children was 26% after two febrile UTIs and the odds of renal scarring was 12 times greater after a second infection than after a single febrile UTI.

A 2016 study demonstrated that a delay in the initiation of antimicrobial therapy was significantly associated with the development of renal scarring in children with febrile UTI. A delay of 48 hours increased the risk for renal scarring by 47%, at a rate of 1% per hour (from an overall prevalence of 5%-7.5%). Before the advent of antimicrobial therapy, up to 20% of children hospitalized for pyelonephritis died from the disease.

Epidemiology

Younger children are more likely to have UTIs accompanied by fever than older children. The overall prevalence of having a febrile UTI before age 19 years is nearly 8%. At age 0-3 months, uncircumcised boys have a higher rate of febrile UTIs than girls. By age 6 months, the rate of febrile UTIs in boys decreases and the rate in girls is higher.

Pathogenesis

Acute pyelonephritis occurs when bacteria ascend to the kidneys or arrive in the kidneys via hematogenous spread, causing intrarenal infection. Escherichia coli bacteria with P fimbriae attach to uroepithelial cells and cannot be flushed out. The endotoxin (lipopolysaccharide) of the bacteria binds to CD14 on the cell surface, activating toll-like receptor (TLR) 4. Through subsequent steps, this activates transcription factor nuclear factor kappa-B (NF-κB), which migrates into the cell nucleus, stimulating production of inflammatory factors, including cytokines, chemokines, nitric oxide, and transforming growth factor β. These mediators induce an inflammatory response, which increases vascular permeability and recruitment of neutrophils to resolve the infection, but the mediators are also responsible in part for the ensuing kidney scarring. Abbreviations: COX-2, cyclooxygenase-2; I-κB, inhibitory protein kappa-B; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor-alpha (Source: Febrile Urinary Tract Infections in Children. N Engl J Med 2011.)

The above figure shows the current approach (blue) to febrile urinary tract infection (UTI) in children and highlights the contribution of congenital damage and the importance of immunologic and genetic factors (red). The figure also recognizes the role of infection-related kidney scarring in producing major long-term medical sequelae. Genetic factors influence both the occurrence of dysplasia and the propensity for scar formation. The role of antibiotic prophylaxis that is depicted here represents our view. Abbreviations: VUR, vesicoureteral reflux; VUR III-V, grade III to grade V reflux (Source: Febrile Urinary Tract Infections in Children. N Engl J Med 2011.)

Risk Factors

Risk factors for UTIs include certain innate host-susceptibility factors and several external or genetic causes as described below:

Anatomy

Circumcision status: Based on primary data, young uncircumcised boys are at higher relative risk of UTI than circumcised boys. Two proposed mechanisms for the increased risk are:

• The mucosal surface of uncircumcised glans has more uropathogenic bacteria near the urethral meatus in infancy. The bacteria decrease by 1 year of age as the keratinization completes, coinciding with a decreasing prevalence of UTI in boys.

• A tight foreskin may partially obstruct the meatus. This typically improves after a few months to 1 year of age, diminishing the occurrence of UTIs.

One large meta-analysis demonstrated that circumcision was associated with an overall risk reduction in UTIs of approximately 90%. However, the number needed to treat to prevent a single UTI was 111 in that study. The overall incidence of UTI in uncircumcised boys is low (estimated rate, 7 per 1000 person years versus 1 per 1000 person years in circumcised boys). Hence, the choice for circumcision in developed countries is still recommended to be based on parental and cultural preference.

Congenital anomalies of kidney and urinary tract (CAKUT):

Anomalies in normal embryonic development of the genitourinary tract that lead to urinary retention or lack of normal emptying could theoretically increase the risk of infection. (See CAKUT in this rotation guide for descriptions of anomalies of the genitourinary tract.) Four of the more common types of CAKUT can logically increase risk for UTI:

• Vesicoureteral reflux (VUR) is graded according to severity from grade I (mild) to grade V (severe) and can lead to urine refluxing back toward the kidney from the bladder and predispose patients to infection.

• Posterior urethral valves (PUVs) can lead to urinary obstruction that can cause chronic kidney disease, end-stage kidney disease, and chronic infection caused by an inability to empty the bladder properly.

• Ureteropelvic junction obstruction (UPJO) can lead to hydronephrosis and subsequent urinary stasis within the collecting system and result in infection.

• Multicystic dysplastic kidney (MCDK) is accompanied by VUR on the contralateral side in 10%-20% of cases.

Obstruction:

Any obstruction that prevents bladder emptying may increase the risk of infection (similar to CAKUT).

• Neurogenic bladder: Patients with myelomeningocele or other causes of neurogenic bladder can have an increased risk of UTI if they are incontinent or cannot empty their bladder properly. Many of these patients also require catheterization for voiding. Introducing a catheter at regular intervals, even if done in a sterile fashion, is an infection risk.

• Bladder and bowel dysfunction (BBD): BBD is a distinct entity that should be considered by all pediatricians as they evaluate patients. This clinical finding can manifest as a chief complaint for poor school performance, enuresis, frequent urination and voiding, and abdominal pain, as well as UTI. BBD is defined as any abnormal urinary or stooling pattern, including problems with voiding (infrequent or too frequent, daytime accidents, or withholding maneuvers). Abnormal stooling, such as constipation, is a common coexisting finding that can exacerbate symptoms of dysfunctional voiding. Several studies detail an increased risk of UTI associated with BBD, irrespective of other risk factors, such as VUR. (See BBD in this rotation guide for further information.)

Sexual activity:

Patients who are sexually active are at increased risk for UTI. Furthermore, spermicidal contraceptives may increase risk by altering the vaginal flora.

Guidelines

The American Academy of Pediatrics (AAP) and the National Institute for Health and Care Excellence (NICE, UK) have published guidelines that outline recommendations for diagnosis and treatment of UTI in children. This brief review focuses on the AAP guidelines.

Summary of the AAP Guidelines for Diagnosis of UTI in Children

If a UTI is suspected, urine should be obtained for both urinalysis and culture before antibiotics are initiated.

Urinalysis and microscopy:

• Urine should be fresh when analyzed; it should be examined within 1 hour if freshly obtained and not refrigerated and within 4 hours if it has been refrigerated promptly after being obtained.

• Urinalysis dipstick testing for leukocyte esterase and nitrites has been around since the 20th century.

• The enzyme leukocyte esterase, which is produced by white blood cells, is detectable with a dipstick and may be used as a surrogate marker for pyuria.

• The nitrite test relies on the fact that infection by gram-negative rod (GNR) bacteria can convert nitrates to nitrites. Note: For nitrites to be detectable in urine obtained by voiding, bladder catheterization, or aspiration, approximately 4 hours will have had to elapse in order for nitrates to be converted to nitrites. Infants and young children who are not toilet-trained void frequently; thus, the urine may not stay in the bladder long enough for the nitrite test to be positive, even in in the presence of a bacterial infection due to gram-negative rods.

• On urine microscopy, pyuria is defined by more than five white blood cells per high-power field.

Sampling method and culture:

• Urine culture should be obtained via a clean-catch specimen or by obtaining a catheterized or suprapubic aspiration (SPA) in patients who are not yet toilet-trained.

• A urine bag specimen is not appropriate for the diagnosis of UTI. However, in certain situations depending on parent and clinician preference, a reasonable approach is to obtain a urine bag specimen for urinalysis and microscopy before determining if a catheterized specimen or a bladder tap is necessary.

  • Appropriate situations for obtaining a urine bag specimen include children with lower pretest probability (e.g., a circumcised boy with a fever <39°C and a sibling with a concomitant viral illness).

  • If the urinalysis demonstrates leukocyte esterase or nitrite positivity, or abnormalities such as pyuria or bacteriuria on microscopy, then an SPA (bladder tap) or catheterized urine specimen should be obtained.

  • However, waiting for a bag urine followed by obtaining a catheterized/SPA sample can cause a delay in diagnosis/disposition.

Definition of UTI diagnosis:

• Requires evidence of bacteriuria/pyuria on urinalysis AND culture >50,000 colony-forming units (CFUs) per mL via catheterization.

• Colony counts <50,000 CFUs per mL can be considered positive if obtained via SPA.

Summary of the AAP Guidelines for Treatment of UTI in Children

Antibiotic treatment: Based on the AAP guidelines and available data, parenteral and oral therapy are equally efficacious; the choice to start or switch to an oral agent should be based on whether the patient can tolerate oral therapy.

• Duration of antibiotic treatment: Although no evidence-based guidelines exist for duration of antibiotic treatment, the AAP consensus-based guidance recommends a course ranging between 7 and 14 days. Trials to examine the efficacy of a shorter (5-day) course of therapy in children with febrile UTIs have demonstrated that a shorter course of antibiotic therapy is inferior to standard of care.

• Empiric antibiotic choice should be based on the antibiogram at local institutions due to geographical differences in sensitivities and take into account the patient’s past urine culture results, if any. An antibiogram is a report or chart that shows how susceptible certain bacteria are to a specific antibiotic or class of antibiotics, based on isolates found in the hospital.

• Assessment for underlying conditions: Clinicians should assess for and address any underlying bladder and bowel dysfunction (see BBD section in this rotation guide).

Alternative therapies: The AAP guidelines do not address alternative or adjuvant therapies for UTI. Cranberry juice or extracts have been thought to be beneficial in the prevention of UTI but a recent Cochrane review did not find any evidence to support its use. However, results of a recent trial suggested that corticosteroids may be useful to prevent renal scarring, but larger studies are still needed to confirm this finding.

Imaging and antibiotic prophylaxis: The role of imaging and prophylaxis in children with febrile UTI remains controversial among nephrologists, urologists, infectious disease specialists, and radiologists. Options for imaging in UTI include:

• Renal and bladder ultrasound (RBUS):

  • All children aged 2-24 months with febrile UTI should undergo RBUS to detect anatomic abnormalities. RBUS is not a good screening test for VUR.

  • Discussion is ongoing about the cost effectiveness of RBUS following a first febrile UTI.

  • RBUS should be performed subacutely unless a child is clinically ill or not improving with treatment.

  • RBUS is not associated with radiation risk.

• Dimercaptosuccinic acid (DMSA) scan:

  • This nuclear medicine test is useful in research to show pyelonephritis and scarring as a later outcome. It rarely changes acute clinical management. However, results of a recent study suggested that DMSA has a role in the management of patients with febrile UTI.

  • DMSA scan is associated with approximately 1-2 millisieverts (mSv) of radiation (equivalent to 50-100 chest radiographs).

• Voiding cystourethrogram (VCUG):

  • VCUG definitively diagnoses VUR.

  • Only recommend VCUG screening after a second febrile UTI or if the RBUS is abnormal.

  • VCUG is associated with approximately 0.03-0.1 mSv radiation (3-5 chest radiographs) using modern grid-controlled pulse fluoroscopy.

Routine VCUG screening:

• The AAP UTI guidelines released in 2011 and reaffirmed in 2016 do not recommend routine VCUG screening in children after the first febrile UTI. However, this recommendation is based on analysis of data available in 2011 that indicated that children with known VUR who received antibiotic prophylaxis did not have a significant reduction in recurrent UTIs.

• In 2012, the AAP Section on Urology stated that they did not support the AAP VCUG screening recommendations and believed that VCUG should remain an option after febrile UTI. The AAP subcommittee that published the guidelines supported their recommendation in a response to the Section on Urology.

• In 2014, new data from the RIVUR trial indicated a significant reduction in recurrent UTI in children with VUR who received antibiotic prophylaxis, compared with those who did not. The RIVUR trial authors suggested that their results might warrant reconsideration of the AAP recommendations. But, after the RIVUR trial data were released, the AAP reaffirmed its recommendations, prompting the RIVUR trial authors to respond in lieu of several criticisms of their paper and the AAP recommendations.

Note: When it comes to the topic of VCUG and antibiotic prophylaxis, clinicians will need to review the available data and come to a conclusion in discussions with patients and families.

Kaplan-Meier estimates of the cumulative percentage of children who had a recurrent febrile or symptomatic UTI according to study group. Fewer children assigned to TMP-SMX prophylaxis had a UTI than children assigned to placebo (P<0.001 by log-rank test). I bars indicate 95% confidence intervals. (Source: Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. N Engl J Med 2014.)