UTIs in children

Authors

Stephen S. Yang (Division of Urology, Taipei Tzu Chi Hospital, Medical Foundation, New Taipei;Buddhist Tzu Chi University, Hualien, Taiwan)

Chang-Hee Han (Department of Urology, Uijeongbu ST. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Republic of Korea)

Jeng Daw Tsai (Department of Medicine, Mackay Medical College; Department of Pediatric Nephrology, MacKay Children's Hospital; Department of Pediatrics, Taipei Medical University Hospital, Taipei; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taiwan)

Akihiro Kanematsu (Department of Urology, Hyogo College of Medicine, Hyogo, Japan)

Executive summary

Epidemiology and pathogenesis

1. Classification according to the sites of infection (lower tract versus upper tract), the number of episode (first versus recurrent), the severity (simple versus severe), or the existence of complicating factor (uncomplicated versus complicated) is useful to differentiate children with UTI whether they are at risk of renal damage or not (LE: 2, GR: B).

2. The presence of UTI should be considered on the basis of clinical presentation, the age of the child, and the severity of the disease. However, clinical symptoms/signs are not sufficiently accurate to definitively diagnose UTI (LE: 1a, GR: A).

Diagnosis

1. Diagnosis of UTI requires both urinalysis that suggests infection and positive urine culture (LE:3, GR B). For pre-toilet trained children, urine specimen for culture should be collected by urethral catheterization or suprapubic aspiration. For toilet trained children, midstream clean catch urine is reliable (LE: 3, GR: A). Urine culture is considered positive if it demonstrates growth of a single bacterium with the following colony counts: (1) any growth by suprapubic aspiration, (2) >5 x 10⁴ CFU/ml by urethral catheterization, or (3) >10⁵ CFU/ml by midstream clean catch (LE:3, GR: B).

2. The goals of imaging studies are to localize the infection (lower or upper tract UTIs), to demonstrate anatomical or functional abnormalities, to detect significant VUR, and to detect congenital or acquired renal scarring (LE: 2, GR: B).

3. For children with febrile UTI, renal and bladder ultrasonography (RBUS) should be routinely performed as soon as possible (LE: 3, GR: C). RBUS should be followed up 6 months later in children with acute pyelonephritis and/or VUR (LE: 3, GR: C).

4. Acute DMSA scan can be performed when severe acute pyelonephritis or congenital hypodysplasia is noted on RBUS or when the diagnosis of UTI is in doubt by the clinical presentation (LE: 3, GR: C). Late DMSA scan (> 6 months after the febrile UTI) can be performed in children with severe acute pyelonephritis, high-grade VUR, recurrent febrile UTIs, or abnormal renal parenchyma on the follow-up RBUS (LE: 3, GR: C).

5. Top-down or bottom-up approach for febrile UTI is suggested for the diagnosis of VUR. For top-down approach, VCUG should not be performed routinely for children after the first febrile UTI. VCUG is indicated when abnormalities are apparent on either RBUS or DMSA scan or both (LE: 2, GR: B). VCUG is also suggested after a repeat febrile UTI (LE:2, GR: B). The bottom-up approach consists of a RBUS and a VCUG for the initial investigation for febrile UTI (LE: 2, GR: B).

Treatment

1. Appropriate antibiotic should be given immediately after urine specimen for culture has been obtained (LE:2, GR: A). Initiating therapy with oral or parenteral antibiotics is equally efficacious for children (> 3 months) with uncomplicated UTI (LE: 2: GR: A).

2. The choice of empirical antibiotic agents is guided by the expected pathogen and the local resistance patterns (LE: 2, GR: A). For children with febrile UTI, the total course of antibiotic therapy should be 7-14 days (LE: 2, GR: B).

3. The potential benefit of preventing recurrent UTI by antimicrobial prophylaxis should be weighed against the risk of antimicrobial resistance with future infections. (LE: 2, GR: B)

4. Antimicrobial prophylaxis to prevent recurrent UTI may be considered in infants and children with or without vesicoureteral reflux (VUR) after a first UTI. (LE: 1b, GR: B)

5. Circumcision may, but not definitively, reduce the risk of febrile UTI in males and breakthrough febrile UTI in males with VUR. Circumcision should be offered to uncircumcised boys with febrile UTI and VUR in countries where circumcision is accepted by the general population (LE: 3, GR: B), while in countries where childhood circumcision is rarely performed, other measures for febrile UTI/VUR should be the preferred choice (LE: 4, GR: C).

6. BBD is one of the key factors of progression of renal scarring (LE: 2). Early recognition and management of LUTD and bowel dysfunction are important in prevention of UTI recurrence (LE:2, GR: A).

7. Despite the concerns about ionizing radiation and its invasive nature, conventional VCUG remains the gold standard to detect VUR because the test allows better determination of the grade of VUR (in a single or duplicated kidney) and better assessment of bladder and urethral configuration (LE: 2, GR: B).

8. Antibiotic prophylaxis to prevent recurrent febrile UTI is indicated in children with moderate to high grade (III-V) VUR (LE: 1b, GR: A).

9. Surgical intervention should be used to treat VUR in the setting of recurrent febrile UTI because it has been shown to decrease the incidence of recurrent pyelonephritis (LE: 2, GR: B).

Prevention

1. Bladder dysfunction increases the risk of UTI and can lead to significant delay in resolution of VUR. (LE: 2, GR: B)

2. Breast feeding may protect infants from UTI (LE: 2), and is strongly recommended for prevention of UTI in infants (LE: 3, GR: A).

3. Cranberry and related products may prevent UTI in children (LE: 3) and may be considered in the prevention of UTI in children (GR: C).

4. Probiotics may prevent UTI in children and in children (LE: 3) and may be considered in the prevention of UTI in children (GR: C).

Introduction

Urinary tract infection (UTI) is a common infection in children and infants around the world.

Many existing guidelines for pediatric UTI come from Western countries. To our knowledge, only few guidelines come from Asian countries. Management of pediatric UTI should be based on scientific evidence and tailored to local cultural and social environment.

UTI represents the most common bacterial infection in children ≦2 years of age^[1] (LE: 2a). The outcome of UTI is usually benign, but in early infancy, it can progress to renal scarring, especially when associated with febrile UTI. Delayed sequelae related to renal scarring include hypertension, proteinuria, renal damage and even chronic renal failure in a significant number of adults^[2] (LE:2a). The risk of UTI during the first decade of life is 1% in males and 3% in females^[3]. The incidence of UTI is higher in boys than girls ≦3 months of age. The overall recurrence rate for the neonatal period has been reported to be 25% and that for toilet trained children is 30-50%^[3][4].

The common pathogens are Gram-negative, mainly enteric, bacteria. Of these, E. coli is responsible for more than 80% of UTI episodes^[5]. The urinary tract is a sterile space with an impermeable lining. Retrograde ascent is the most common mechanism of infection. Nosocomial infection and involvement as part of a systemic infection are less common^[6].

Risk factors for the development and recurrence of UTI should be explored and managed. Neurogenic and non-neurogenic lower urinary tract dysfunction may lead to elevated post-void residual urine (PVR) and secondary VUR^[4]. Comprehensive approach for UTI in children without neuropathic bladder is summarized in Figure 1.

Figure 1. Comprehensive approach for risk factors and treatment for pediatric febrile UTI

Classification of Urinary Tract Infections in Children

Summary of Recommendations

Classification according to the sites of infection (lower tract versus upper tract), the number of episode (first versus recurrent), the severity (simple versus severe), or the existence of complicating factor (uncomplicated versus complicated) is useful to differentiate children with UTI whether they are at risk of renal damage or not (LE: 2, GR: B).

Introduction

Many classification systems have been introduced to identify children with UTI whose kidneys are at risk or not. UTIs can be classified by the site of infection (lower tract versus upper tract), by the number of episode (first versus recurrent), by severity (simple versus severe), by the presence of symptoms (asymptomatic versus symptomatic), or by the existence of complicating factor (uncomplicated versus complicated) (Table 1). Such classifications imply severity of infection when, in fact, this cannot be documented clinically nor may “milder” infections require less rigorous evaluation.

Table 1. Classifications of urinary tract infections in children

Classification according to site of UTIs

Understanding and appropriately differentiating cystitis from pyelonephritis is crucial and imperative for two reasons: (a) to permit identification, treatment, and evaluation of the children who are at risk for kidney damage; and (b) to avoid unnecessary evaluation and treatment of children who are not at risk.

Classification according to the number of UTI episode

UTI can be cateGR:ized as first infection and recurrent infection. The recurrent UTIs can be subcategorized further as unresolved bacteriuria, bacterial persistence, or reinfection^{[7][8][9][10]}.

First infection is simply the initial UTI that is diagnosed. Recurrent infection can be subgrouped as unresolved infection, bacterial persistence and reinfection. Unresolved infection indicates that initial therapy has been inadequate in eliminating bacterial growth in the urinary tract. Bacterial persistence is caused by reemergence of bacteria from a site within the urinary tract and may be due to a nidus for persistent infection that cannot be eradicated. As a result, the same pathogen is identified in recurrent infections, but episodes of sterile urine may occur during and shortly following antimicrobial treatment. Bacteria reside in an isolated portion (or anomaly) of the urinary tract where the pathogens are shielded from the current treatment, resulting in a persistent nidus of infection (e.g., infected staghorn stones, Table 2)^[7].

Table 2. Surgically correctable causes of bacterial persistence in children

Reinfection is different from bacterial persistence. In reinfection, each episode can be caused by a variety of new infecting organisms, whereas in bacterial persistence, the same infecting organism is always isolated. Reinfection most frequently occurs by the fecal-perineal-urethral route in girls and periurethral colonization in boys. Confusion in this form of pathogenesis sometimes occurs because Escherichia coli, the most common general pathogenic species which exist in many different serotypes. Thus, recurrent Escherichia coli UTI does not equate to infection with the same organism. With serotyping, reinfection can be established, but this is done rarely in the routine clinical setting.

Classification according to severity of UTIs

From the clinical point of view, simple and severe forms of UTIs should be differentiated because to some extent the severity of symptoms dictates the degree of urgency with which investigation and treatment are to be undertaken (Table 3).

Table 3. Clinical classification of pediatric urinary tract infections (UTIs) according to severity

Classification according to symptom

This classification system is based on the existence of local or systemic symptoms.

Classification according to complicating factor

Useful criteria for distinguishing complicated from uncomplicated UTI are summarized in the Table 4^[11].

Table 4. Clinical classification of pediatric urinary tract infections according to complication factors

Conclusions

For the practical purposes, four kinds of classification (lower tract versus upper tract, first versus recurrent, simple versus severe or uncomplicated or complicated) are widely used. Such classifications are based on the natural history and subsequent evaluation and management which imply possibility of complication.

Diagnosis of the initial UTI in infants and children

Summary of Recommendations

1. Clinical symptoms and signs

The presence of UTI should be considered on the basis of clinical presentation, the age of the child, and the severity of the disease. However, clinical symptoms/signs are not sufficiently accurate to definitively diagnose UTI (LE: 1a, GR: A).

2. Urinalysis and urine culture for diagnosis of UTI

Diagnosis of UTI requires both urinalysis that suggests infection and positive urine culture (LE: 3,GR B). For pre-toilet trained children, urine specimen for culture should be collected by urethral catheterization or suprapubic aspiration. For toilet trained children, midstream clean catch urine is reliable (LE: 3, GR: A). Urine culture is considered positive if it demonstrates growth of a single bacterium with the following colony counts: (1) any growth by suprapubic aspiration, (2) >5 x 10⁴ CFU/ml by urethral catheterization, or (3) >10⁵ CFU/ml by midstream clean catch (LE: 3, GR: B).

UTI is a common serious bacterial infection in childhood. Accurate and timely diagnosis and treatment is important for the prevention of long-term morbidity and sequelae (e.g.hypertension, proteinuria, and chronic kidney disease). The symptoms and signs of UTI are very broad and largely depend on the age of the patients. Young children with UTI may present nonspecific symptoms. Fever may be the sole presentation in young infants and is considered as an important marker of renal parenchymal involvement. Among children 2 to 24 months of age with a fever without obvious source, prevalence of UTI is about 5% ^[12]. Neonates and young infants with febrile UTI are more likely to have bacteremia or sepsis than older children and should be carefully evaluated and managed^[13]. UTI in infants can manifest as diverse and non-specific symptoms. Fever, sepsis, lethargy, prolonged jaundice, hematuria, poor feeding, vomiting, diarrhea, irritability, failure to thrive, cloudy or malodorous urine, and crying on passing urine are the possible presentation in newborn and young infants. Older children are able to verbalize better specific symptoms, such as dysuria, frequency, urgency, new onset urinary incontinence, abdominal or flank pain, suprapubic discomfort, and vomiting. In older children, the presence of specific urinary symptoms can be used as a criterion for further examination^[14]. A critical review concluded that although individual symptom and sign were helpful in the diagnosis of UTI, no individual symptom/sign or any combination of them were sufficient enough to identify children with UTI^[15].

Investigation for UTI starts by examining the urine. For pre-toilet trained children, urinalysis and urine culture can be collected from suprapubic aspiration or urethral catheterization when the child is ill and require immediate antibiotic therapy. A fresh bag urine specimen can also be used and examined as an initial screening tool. Numerous studies and meta-analyses have examined their accuracy to predict or exclude UTI in children (Table 5)^[16][17]Finnell 2011). To diagnose UTI, urinalysis should focus on biochemical analyses of leukocyte esterase and nitrite through a rapid dipstick method and urine microscopic examination for pyuria and bacteriuria. Positive leukocyte esterase is comparable to pyuria (WBC≧ 5/HPF) by microscopy. False positive results may be caused by external contamination (vulvovaginitis), viral infection (roseola infantum), Kawasaki disease, acute appendicitis, or vigorous exercise. Nitrite test has a low sensitivity (about 50%) but high specificity (98%) for pediatric UTI. Therefore, negative result of nitrite test does not rule out UTI. However, when the test is positive, UTI is very likely. A recent study shows dipstick may be an adequate screening test for UTI with a negative predictive value of 98.7%. Adding microscopy increases the negative predictive value to 99.2% but results in 8 false-positive tests for every UTI missed by dipstick^[18]. Enhanced urinalysis by hemocytometer (≧ 10 WBC/μL in a counting chamber or any bacteria found in 10 oil emersion fields) has greater sensitivity and specificity than standard urinalysis (Table 5) ^[19][20].

Table 5. Diagnostic value of dipstick and microscopy for the diagnosis of urinary tract infections

Physical examination should include determining the presence of phimosis, labial adhesion, and any stigmata of spinal bifida. Nonspecific tests of inflammation (such as elevated peripheral white blood cell count, C-reactive protein, or sedimentation rate) can provide helpful guidance.

However, they are not considered useful diagnostic tools to identify acute pyelonephritis because of a low specificity[21]. Procalcitonin is considered the best parameter to predict the presence of renal parenchymal involvement^[21].

Without contamination of perineal flora, suprapubic aspiration has been considered the standard method for urine culture in young children. Urine specimen via catheterization is associated with a higher success rate and less pain than suprapubic aspiration (Finnell, 2011). Suprapubic aspiration and transurethral catheterization are strongly recommended from 2011 AAP guidelines for children aged 2-24 months^[17]. For toilet trained children, urine specimen for culture can be obtained by midstream. Urine cultures collected from a bag applied to the perineum is not suggested due to unacceptably high false-positive rates (85%) (Finnell 2011).

Definitions of positive or negative culture results are related to the methods of collection. The distal urethra or perineal area is always colonized by some fecal bacteria. Although bacteria are not present in bladder urine, a low colony count may be present in a specimen collected through voiding or catheterization. As a result, a significant colony count depends on the method of urine collection and clinical symptoms. The cutoff values for positive culture results are operational and not absolute. In the 1950s, Kass in his study on adult women established the threshold of 10⁵ CFUs/ml in a voided specimen to define a positive urine culture^[22]. In young children, urine is usually collected by catheterization, the cutoff for defining UTI is always considered 10⁴ CFUs/ml^[23][24]). However, Hoberman et al. noted that a high proportion (65%) of cultures with colony counts between 10⁴ and 5 x10⁴ grew mixed organisms suggestive of contamination(Hoberman 1996). Different cutoff values for positive cultures obtained by bag, midstream, catheterization, and suprapubic aspiration have been defined based on contamination risk of specimens. Most guidelines suggest any bacterial growth from suprapubic specimens is clinically significant. Table 6 shows the criteria for UTI diagnosis based on the bacteria colony counts in urine specimen and urinalysis in recent UTI guidelines.

Table 6. Criteria for UTI diagnosis based on the bacterial colony count in urine cultue

AAP: American Academy of Pediatrics

CCMHG: Cincinnati Children's Hospital Medical Center

EAU: European Association of Urology

Like the recommendations of 2011 AAP guidelines, our criteria suggest the definitive diagnosis of UTI is made on the basis of quantitative urine culture and positive results on urinalysis. It is now recognized that the presence of white blood cells is an important feature of true UTI. Pyuria is a hallmark of UTI and helps to distinguish UTI and asymptomatic bacteriuria. Asymptomatic bacteriuria will have no pyuria, despite the positive urine culture. Asymptomatic bacteriuria is caused by bacterium of low virulence that colonizes the urinary tract and does not damage the kidney. Studies showed that antibiotic treatment for children with asymptomatic bacteriuria may do more harm than good^[25].

Antimicrobial Therapy

Summary of Recommendations

1. Appropriate antibiotics should be given immediately after urine specimen for culture has been obtained (LE: 2, GR: A). Prompt treatment of a febrile UTI is important to eradicate the acute infection, to prevent bacteremia, to improve the clinical condition, and possibly to reduce the likelihood of renal damage (LE: 2, GR: B). The determination of route of administration, antibiotic of choice, and duration of treatment depends on the location of infection, age of patients, severity of presentation, and the antibiotic resistance pattern in community (LE: 2, GR: A).

Initiating therapy with oral or parenteral antibiotics is equally efficacious for children (> 3 months) with uncomplicated UTI (LE:2, GR: A).

2.The choice of empirical antibiotic agents is guided by the expected pathogen and the local resistance patterns (LE: 2, GR: A). Final antibiotic of choice should be adjusted to the narrowest spectrum antibiotic when susceptibility result is available (LE: 2, GR: B). For children with febrile UTI, the total course of antibiotic therapy should be 7-14 days (LE:2, GR: B).

In a child with suggestive clinical symptoms and positive urinalysis findings, empiric antibiotics should be initiated after appropriate urine specimen for culture has been obtained. Timely and appropriate diagnosis and prompt treatment of a febrile UTI is important to eradicate the acute infection, to prevent bacteremia (in particular, young infants less than 3 months of age), to improve the clinical condition, and possibly to reduce the likelihood of renal damage, although it was not confirmed in all studies^[26][27].

Treatment of UTI depends on location of infection (upper or lower tract infection), age of patients, severity of presentation, and the antibiotic resistance pattern in community. For afebrile bacterial cystitis in children, orally administered antibiotics for 2-4 days are generally adequate and are as effective as those given for 7-14 days^[28]. For uncomplicated febrile UTI, the results of the oral versus intravenous route do not differ regardless of the duration of fever, recurrence of UTI and incidence of subsequent kidney damage (renal scarring) after infection (GR: A)^[29][30][31].

Meta-analysis for treatment of acute pyelonephritis in children concludes that oral therapy is appropriate when tolerated, and suggests treatment duration of 7-14 days (Hodson, 2007;Roberts, 2011). When initiating treatment, the choice of oral or parenteral antibiotics is based on age, clinical suspicion of bacteremia, toxic presentation, refusal of fluid or medication (vomiting or diarrhea), non-compliance, or complicated UTI. In general, oral antibiotics can be used effectively on an outpatient basis to treat uncomplicated UTI in children > 3 months who are clinically stable (GR: A). For young infants < 3 month of age, data on oral therapy is limited. Considering the increased incidence of urosepsis and severe infection (10%)^[26], we recommended initial hospitalization and parenteral antibiotic therapy after complete septic workup for infants at this age (GR: C). Therefore, indications for hospitalization in children with febrile UTI include infants < 3 months, severely ill children, laboratory evidence of severe infection, immunocompromised children, intolerance to oral intake, concern of noncompliance, previous history of urinary tract anomalies, or failure to respond to oral antibiotics (GR: C).

Common uropathogens include Escherichia coli (accounting for more than 80% organisms causing UTIs in children), Klebsiella, Proteus, Enterobacter, Enterococcus, Citrobacter, and Staphylococcus saprophyticus (adolescent girls)^[32][33]. It is reported that UTIs caused by enterococcus is associated with more underlying urinary tract anomalies than gram-negative UTI and more inappropriate antibiotic therapy, which need adequate imaging and antibiotic therapy^[34]. Less common organisms such as Pseudomonas, Staphylococcus aureus, or Staphylococcus epidermidis are seen with increased frequency in children with anatomic anomalies, following genitourinary surgery or bladder catheterization, and following repeated courses of antibiotic treatments. Antibiotic resistance is a growing problem, especially for children receiving prophylactic antibiotics for VUR. Evidence suggests that age less than 1 year and recurrent UTIs appear to be independent risk factors for UTI caused by bacteria that produce extended-spectrum beta-lactamase (ESBL)^[35]. They are more likely to have ESBL UTI when prophylactic cephalosporine is used^[36]. The selection of empirical antibiotics is guided by local antimicrobial sensitivity patterns, but coverage for Escherichia coli as the leading pathogen should be considered. Some experts suggest using oral or parenteral third-generation cephalosporines as the initial treatment. But these cephalosporines are broad-spectrum agents.

Injudicious use of these broad-spectrum antibiotics may increase the resistance rates of uropathogens. When antibiotic susceptibility results from urine culture are available, therapy should be adjusted to the narrowest spectrum antibiotic. Oral quinolone antibiotics(ciprofloxacin), which are not licensed for use in prepubertal children, are highly efficient against most uropathogens. Its use should remain a choice for mutidrug-resistant pathogens (GR: C). Traditional first-line antibiotic for childhood UTI, such as cotrimoxazole, with resistance rates of more than 50% in Taiwan, has been rendered inadequate^[37]. The usual choices for oral antibiotics include a first-generation cephalosporine or amoxicillin-clavulanic acid. Agents do not achieve therapeutic concentrations in the bloodstream, such as nalidixic acid or nitrofurantoin, should not be used to treat young children with febrile UTI, because their serum and parenchymal concentrations may be insufficient to treat sepsis or pyelonephritis (Roberts, 2011).

When intravenous treatment is required, initial combination treatment with ampicillin and an aminoglycoside (e.g. gentamicin) or cephalosporine achieves excellent therapeutic results(aminoglycosides or cephalosporine against most common gram-negative uropathogens and amipicillin against enterococcus). About 90% of febrile young children with UTIs will be afebrile within 48 hours of initiating appropriate parenteral treatment ^[38]. Repeat urine culture seems not to be needed in children with good clinical response (Roberts, 2011). Antibiotics can be administered parenterally for 2-4 days, followed by oral antibiotic course. Prolonged fever occurs in older children or children with lobar nephronia, renal abscess, pyonephrosis, immunodeficiency, inadequately treated infection caused by multi-resistant bacteria[38]. The total course of antibiotic therapy should be 7-14 days, whether the initial route of administration of antibiotics is oral or parenteral (then change to oral) (GR: B) (Roberts, 2011). Data comparing the efficacy of 7 days, 10 days and 14 days are not available.

More severe parenchyma infections, such as acute lobar nephronia or renal abscess, require longer antibiotic course of >14 days^[39]. Preliminary study shows adjunctive oral methylprednisolone may reduce renal scarring after acute pyelonephritis[40]. However, the evidence is still limited due to the small number of study children.

Continuous Antimicrobial Prophylaxis

Summary of Recommendation

1. The potential benefit of preventing recurrent UTI by antimicrobial prophylaxis should be weighed against the risk of antimicrobial resistance with future infections. (LE: 2, GR: B)

2. Antimicrobial prophylaxis to prevent recurrent UTI may be considered in infants and children with or without vesicoureteral reflux (VUR) after a first UTI. (LE: 1b, GR: B)

Introduction

Recurrent UTI may develop in 30-50% of children with episode of symptomatic UTI1,2^[41][42] and the recurrence rate is directly correlated with the number of preceding UTIs3^[43]. The susceptibility for recurrences is highest within the first 2 to 6 months after a UTI4^[44]. A long term antimicrobial prophylaxis is considered in cases of high susceptibility to UTIs and risk of acquired renal damage. These include patients with dilating high grade VUR, with recurrent pyelonephritic episodes or with significant urinary tract obstruction.

Selection of Antimicrobials

Antimicrobials selected for prophylaxis should fulfil the following demands: (1) effectiveness against the majority of uropathogens, (2) causing a minimum of serious side effects, (3) causing minimal bacterial resistance, (4) making little ecological impact on indigenous bacterial flora.

Usually, the prophylactic antimicrobials are given daily in the evening shortly before sleep with a quarter of the regular therapeutic dosage. Since many years, trimethoprim or cotrimoxazole and nitrofurantoin have been the substances mostly used for antimicrobial prophylaxis of UTI in children. Due to the fact that both substances in many countries are restricted on admission in early infancy, oral cephalosporines are preferred in this age group. Usable antimicrobials for prophylaxis are summarized in the Table 7.

Table 7. Usable substance for antibacterial prophylaxiz

^* Not available in most Asian countries

Controversial issues in antimicrobial prophylaxis

The efficacy of antimicrobial prophylaxis per se has been questioned in several reviews5-8^{[45][46][47][48]}. Recently, several reviews reported that there was no clear association between recurrent UTI and VUR, and renal damage, renal scarring, hypertension, and end-stage renal disease. A 2007 Cochrane review combined the results of two randomized studies (n = 142; median age = three years) comparing antibiotic use with no treatment in prevention of recurrent UTI in children9^[49]. The results showed no difference in the risk of recurrent UTI (RR 0.75; 95% CI, 0.15 to 3.84) or renal damage (RR 1.70; 95% CI, 0.36 to 8.07).

In an updated Cochrane review, six studies of children from birth to 18 years old (n = 1,069) with initial or recurrent UTI compared the effectiveness of prophylactic antimicrobial treatment(ranging from 10 weeks to 12 months) with placebo or no treatment10^[50]. Antimicrobial use did not reduce the risk of symptomatic UTI compared with placebo or no treatment (RR 0.75; 95% CI, 0.36 to 1.53). However, when only studies with a low risk of bias were analyzed, there was a statistically significant reduction in the risk of symptomatic UTI (RR 0.68; 95% CI, 0.48 to 0.95).

The absolute risk reduction was estimated to be 8% (number needed to treat = 13). The authors also found no significant increased risk of resistance to the antimicrobials in the active treatment groups (RR 2.4; 95% CI, 0.62 to 9.26).

A multicenter RCT randomized 100 children younger than 30 months with VUR (grade II to IV) diagnosed after a first episode of acute pyelonephritis to receive trimethoprim/sulfamethoxazole or no treatment for two years11^[51]. There was no reduction in the rate of recurrent pyelonephritis in the treatment group after one year (RR 1.42; 95% CI, 0.76 to 2.65) or after two years (RR 1.25; 95% CI, 0.54 to 2.90). There was no reduction in the incidence of renal damage after two years (RR 1.22; 95% CI, 0.75 to 1.98). Children in the treatment group had recurrent infections caused by multidrug-resistant bacteria: Escherichia coli in 37 cases, Pseudomonas aeruginosa in 3 cases, Enterococcus faecalis in 2 cases, and Morganella morganii in one case. In the control group, all recurrent infections were caused by E. coli, which was 100% sensitive to all antimicrobials tested.

Another prospective multicenter RCT compared the use of prophylactic trimethoprim/sulfamethoxazole with no treatment in 225 children from one month to three years of age with VUR (grade I to III) diagnosed after a first episode of febrile UTI12^[52]. The study concluded that there was no statistically significant reduction of the overall incidence of recurrent UTI with antimicrobial prophylaxis in children with low-grade VUR (17 versus 26%; P = 0.2).

A double-blind RCT randomized 576 children with VUR (median age = 14 months; 71% had first diagnosed episode of UTI) to receive daily trimethoprim/sulfamethoxazole or placebo for 12 months13^[53]. Children in the treatment group had a modest reduction in recurrent UTI; 13% of those in the treatment group developed recurrent UTI compared with 19% in the placebo group(hazard ratio 0.61; 95% CI, 0.40 to 0.93; P = 0.02; number needed to treat = 16). There was a reduction in febrile UTIs in the treatment group (hazard ratio 0.49; 95% CI, 0.28 to 0.86; P = 0.01;number needed to treat = 16). However, the study was underpowered to assess the effect of antimicrobial treatment on long-term renal damage. The incidence of UTI caused by an organism resistant to trimethoprim/sulfamethoxazole was higher in the treatment group (67 versus 25%; P < 0.001). There was no difference between groups in the rate of adverse reactions (P = 0.10) or the rate of hospitalization for UTI (P = 0.38).

Recently, RIVUR trial on antimicrobial prophylaxis for children with VUR was reported14. This multicentric, randomised, placebo-controlled study was designed to examine the effectiveness of antimicrobial prophylaxis in children with reflux who had suffered from UTI. The primary endpoint was the efficacy of antimicrobial prophylaxis in preventing recurrence of febrile/symptomatic UTIs. Secondary end-points were the development of renal scars, treatment failure and antimicrobial resistance. A total of 607 children, aged two to 72 months, with grades I-IV reflux and documented first UTI were included. Recurrent UTI developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (RR 0.55; 95% CI, 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children who presented with febrile index UTI (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively).

Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim–sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. The investigators concluded that among children with VUR after UTI, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring.

Problem of non-compliance

Patient compliance is one of the biggest problems with antimicrobial prophylaxis. Daschner and Marget tested compliance with long-term antimicrobial therapy by urine check in 93 children with recurrent UTIs. Only 32.2% of the children took the prescribed drugs at regular intervals, 19% did not take the antimicrobials at all. Similar results have been shown in children with VUR[54]. Rational and understandable information to the parents about aims and necessity of prophylaxis and its control is inevitable for its success.

Imaging studies after UTI

Summary of Recommendation

1. The goals of imaging studies are to localize the infection (lower or upper tract UTIs), to demonstrate anatomical or functional abnormalities, to detect significant VUR, and to detect congenital or acquired renal scarring (LE: 2, GR: B).

2. For children with febrile UTI, renal and bladder ultrasonography (RBUS) should be routinely performed as soon as possible (LE: 3, GR: C). RBUS should be followed up 6 months later in children with acute pyelonephritis and/or VUR (LE: 3, GR: C).

3. Acute DMSA scan can be performed when severe acute pyelonephritis or congenital hypodysplasia is noted on RBUS or when the diagnosis of UTI is in doubt by the clinical presentation (LE: 3, GR: C). Late DMSA scan (> 6 months after the febrile UTI) can be performed in children with severe acute pyelonephritis, high-grade VUR, recurrent febrile UTIs, or abnormal renal parenchyma on the follow-up RBUS (LE: 3, GR: C).

4. Top-down or bottom-up approach for febrile UTI is suggested for the diagnosis of VUR. For top-down approach, VCUG should not be performed routinely for children after the first febrile UTI. VCUG is indicated when abnormalities are apparent on either RBUS or DMSA scan or both (LE: 2, GR: B). VCUG is also suggested after a repeat febrile UTI (LE:2, GR: B). The bottom-up approach consists of a RBUS and a VCUG for the initial investigation for febrile UTI (LE: 2, GR: B).

The goals for management of childhood UTIs include early and correct diagnosis of UTI, early and appropriate treatment of UTI, recognition and management of acute complications, and assessment of potentially associated structural or functional abnormalities. The past years have brought marked changes in our understanding of the association between UTI, VUR, and renal scarring. With the advancement in evidence-based medicine, some information we used to believe has changed. Traditionally, it has been assumed that VUR is central to the pathogenesis of acute pyelonephritis and subsequent renal scarring after recurrent UTIs and should therefore routinely be screened and aggressively managed[23]. However, VUR is considered merely as one the risk factors for renal damage. Bacterial virulence and host resistance are as potentially important as VUR, if not more important factors.^[55]. In addition to VUR, the other risk factors for scarring include the presence of congenital renal scarring (renal dysplasia), other underlying anatomic abnormalities, bladder bowel dysfunction, gender issues, presence of phimosis, age, delayed treatment of acute pyelonephritis, and recurrent UTIs. Gene polymorphism susceptibility to renal damage on the inflammatory response is also considered an important risk factor for renal damage^[56].

With regard to the significance of VUR in UTI in children, there is no evidence that VUR predisposes to an increased risk of UTI per se. However, it is believed that when infection occurs in a child with high-grade VUR, it is more likely to involve upper rather than lower urinary tract^[57]. VUR is a risk factor for scarring only in the presence of acute pyelonephritis; VUR itself does not directly induce scarring without infection^[58]. Furthermore, about 50% of children with an acute pyelonephritis do not have demonstrable VUR^[59].

Improved prenatal ultrasonography has revealed that major renal damage in children with VUR is frequently related to congenital renal hypo-dysplasia. Renal scars may be congenital or acquired.

High-grade VUR associated with congenital renal hypo-dysplasia (or “congenital reflux nephropathy”) with/without voiding dysfunction is more common in male infants^[60][61][62]. It may occur as part of congenital anomalies of kidney and urinary tract (CAKUT)^[63][64]. The small, poorly functioning kidney with diffuse global photopenia on DMSA scan is clearly not the result of infection. In fact, congenital hypodysplastic kidney is a major cause of chronic renal failure in children who also have VUR^[62]. Acquired segmental scarring as a result of UTI is a different entity. On DMSA scan, it is presented by focal areas of photopenia. It is seen more commonly in older girls with milder reflux. The renal damage in these children is usually minor and rarely causes a reduction in overall renal function. All of current management strategies for VUR are aimed at decreasing acquired scarring.

Therefore, the rationales for imaging studies are to identify risk factors and abnormalities of urinary tract that can be modified to decrease the likelihood of recurrent UTI and subsequent renal scarring. Its aim should be to localize the infection (lower or upper UTIs), to demonstrate anatomical or functional abnormalities (including bladder dysfunction), to detect significant VUR, and to detect congenital or acquired renal scarring.

Although pediatric UTI is a common illness and numerous investigations were reported in literature, the proper approach to imaging evaluation in children with febrile UTI remains controversial. Most practice guidelines recommend either RBUS or technetium-99m-labeled dimercaptosuccinic acid (DMSA) scan combined with voiding cystourethrography (VCUG) [Finnell,2011; Roberts JA, 2011; Ammenti, 2012^[65][66]. The noninvasive nature, lack of radiation, good anatomic demonstration of the entire urinary system, and low cost of RBUS make it an ideal tool for initial screening for anatomic abnormalities in infants with UTI. RBUS provides a general idea of the integrity of the urinary system. Ultrasound scanning is a good tool to assess obstructive uropathies, urolithiasis, ectopic kidney or ureter, posterior urethral valves, and duplication of the collecting system with or without ureterocele. Performance of RBUS during the acute infection is also helpful for detection of renal involvement, suspicion of bladder dysfunction (thickened bladder wall with residual urine), constipation (large rectal diameter) and early recognition of complicated infections such as lobar nephronia and abscess or pyonephrosis. However, acutephase RBUS may increase the false-positive diagnosis of pelvic dilatation [Finnell, 2011]. Early diagnosis of pyonephrosis or abscess is important because percutaneous drainage should be considered to prevent complications when the response to antibiotic treatment is poor [Riccabona, 2007].

However, with the widespread application of antenatal US, the likelihood of detecting obstructive uropathies after UTI is decreased^[67][68]. It is also less reliable for demonstrating APN, renal scarring, and detecting VUR, perhaps because reflux is an intermittent dynamic event. For screening high-grade VUR, in addition to dilated collecting system, other abnormal findings potentially associated with VUR (calyceal or ureteral dilatation, renal hypodysplasia, thickened bladder or pelvis wall, fluctuating renal pelvis) should be included^[69][70]. Regardless of whether VUR is present, other conditions such as acute pyelonephritis, preexisting hypo-dysplasia or scarring, or other obstructive uropathies are also important risk factors for long-term sequelae and should be further followed up.

DMSA renal scan is the gold standard tool for identification of acute pyelonephritis or renal scarring. It can confirm acute pyelonephritis (a focal area of diminished isotope uptake with a preserved renal contour) at the time of acute infection and determine whether a permanent scar(an area with absence of isotope uptake) has occurred 6 months later. As sometimes the clinical symptoms are vague and urinalysis or urine culture is indeterminate (in children who had received antibiotics before urine culture was done), DMSA scan may be useful in confirming or excluding the diagnosis of acute pyelonephritis^[71]. It may also detect the presence of congenital renal hypo-dysplasia, although differentiating renal hypo-dysplasia from infection-related scar is sometimes difficult^[67][72]. Congenital scarring and recurrent UTI constitute a large concern for long-term prognosis and should be followed up. As a result, DMSA scan can be used as a baseline test to compare potential pyelonephritic consequences in the future. An acute DMSA scan is preferred for infants with febrile UTI because they are more likely to suffer more significant morbidity with APN and subsequent renal scarring than are older children, and are less able to communicate their symptoms, leading to a potential delay in diagnosis^[73]. Acute DMSA scan also provides prognostic value. It has been shown that a normal DMSA during an acute febrile UTI with or without reflux is associated with a 0% risk of renal scarring^[74].

Therefore, no further imaging study is needed if RBUS and DMSA are all normal. On the contrary, extensive renal inflammatory involvement with reflux is associated with a high risk of developing renal scars^[74]. However, the use of acute DMSA scan is criticized for higher costs, longer duration, radiation exposure, needing sedation in young children, and requirement of intravenous access and special equipment^[75]. Because acute DMSA scans rarely change immediate management, it is not recommended as part of routine evaluation by AAP guidelines [Roberts KB, 2011], and is listed as an option by AUA and Canadian guidelines^[73]Robinson, 2014]. The Italian guidelines recommend late DMSA (6 months after the febrile UTI) for all children with an abnormal US or in whom VUR has been shown, to obtain a morphologic and functional evaluation [Ammenti, 2012].

Two options are recommended for the diagnosis of VUR: the bottom-up or the top-down approach. The traditional bottom-up approach consists of a RBUS and a VCUG for the initial investigation^[23]. A DMSA scan is recommended in a later stage only in patients with high-grade VUR or with recurrent f-UTIs^[76]. It focuses on diagnosing and managing all-grade VUR. However, VCUG is an invasive procedure with radiation burden, discomfort due to the need for catheterization, and a risk of iatrogenic infection. There is a trend toward using less invasive methods to evaluate children with first febrile UTI and to perform VCUG more selectively. Recent meta-analyses of published data shows that low-grade VUR is of low clinical significance and does not need to be diagnosed and treated^[77][12]. Furthermore, according to the meta-analysis of new AUA guidelines, the risk of acute pyelonephritis (APN) and scarring is considered higher in younger children with grades III–V VUR^[73]. In addition, the effect of prophylactic antibiotic is still in doubt. The “top-down” approach is developed to screen high-grade VUR for children with febrile UTI and reduce the number of VCUG performed [Hansson, 2004; Preda, 2007^{[78][69][79][80][70]}. The advocated approach begins with an acute DMSA scan with or without RBUS, and VCUG performed when the DMSA scan or RBUS is abnormal or there is subsequent recurrent UTI. The top-down approach focuses on renal involvement (congenital hyo-dysplasia or acquired APN) after f-UTI; therefore, a DMSA is obtained first and fewer VCUGs will be performed. However, the meta-analysis study shows the pooled sensitivity and specificity of DMSA scan for detection of high-grade VUR were only 79% and 53%, respectively, for the patient-based analysis^[75]. The study concluded that acute DMSA scan has limited ability to identify risk of high grade VUR.

However, when acute DMSA and RBUS are simultaneously evaluated, an abnormality on either examination has a sensitivity of 83.2-95.3% and a negative predictive value of 91.5-94.3%^[69][79][70]. To avoid inter-observer variability in interpreting RBUS, the examination of RBUS needs standardization. In addition to hydronephrosis, the ultrasonic features have better include calcyceal or ureteral dilatation, variable dilatation of the pelvis, thickened pelvic or ureteral wall, lack of corticomedullary differentiation and cortical hyperechogenicity, small kidneys or cortical thinning with or without tiny cysts, and a thickened or trabeculated bladder wall (features of voiding dysfunction). The other indication for VCUG is recurrent febrile UTI. The risk of highgrade VUR is higher for children with recurrent UTI than for children with a first UTI^[12].

VCUG can be performed as soon as possible provided the inflammation has subsided after treatment [Doganis D, 2009]. It can therefore eliminate the need for antibiotic prophylaxis and increase compliance. VCUG should be carefully interpreted. In addition to detection of VUR, the bladder contour, urethra, and postvoiding residual urine should be evaluated for excluding the possibility of bladder dysfunction, posterior urethral valves, ureterocele, utricle cyst, or neurogenic bladder.

The benefit of top-down approach includes reducing the numbers of VCUG performance and decreased detection and management of clinically insignificant VUR. The disadvantage of topdown approach is associated with higher economic cost, radiation burden, requirement of intravenous access and sedation of young or uncooperative children. A definitive answer to choose which approach method is still lacking, and the multiple determinant factors should be considered, including patient age, VUR grade, presence of renal damage, and recurrence of UTI.

Additional evidence is required to validate any of the suggested approaches. The EAU guidelines recommended initial evaluation with RBUS and VCUG, and the top-down approach was also listed as an option^[76].

Figure 2. Top-down approach for acute imaging algorithm in children with febrile UTI

• Signs of high VUR include hydronephrosis, calyceal or ureteral dilatation, renal hypodysplasia, thickened bladder or pelvis wall, fluctuating renal pelvis

• The diagnosis of mild APN is determined by the clinical presentation and ultrasonic studies.

The general condition of a child with fUTI is good, and the fever is soon controlled after adequate oral or intravenous antibiotics. The RBUS showed only mild or borderline swelling of kidney. For a child with mild APN, the risk of subsequent renal scar is low and therefore acute DMSA can be omitted.

Diagnosis and management of Risk Factors of UTI: Phimosis, Labial adhesion and vulvovaginitis

Summary of Recommendation

1. Circumcision may, but not definitively, reduce the risk of febrile UTI in males and breakthrough febrile UTI in males with VUR. Circumcision should be offered to uncircumcised boys with febrile UTI and VUR in countries where circumcision is accepted by the general population (LE: 3, GR: B), while in countries where childhood circumcision is rarely performed, other measures for febrile UTI/VUR should be the preferred choice (LE: 4, GR: C).

2. Bacterial flora exists in inner prepuce and physicians should be aware that contamination may occur in non-circumcised boys, and catheterization may be required for uncontaminated urine collection. (LE: 2, GR: C)

Circumcision and regional diversity

Febrile UTI is ascending infection of bacteria in the urinary tract, and periurethral bacterial flora has been postulated as the source of pathogenic bacteria in males. Circumcision, surgical removal of prepuce, has been performed as a ritual procedure in selected religions and ethnicities, such as Muslims and Jewish people. Many studies have been published to examine whether this ritual procedure has advantageous effect on prevention of UTI, especially in male infants with VUR. In countries like United States of America, where circumcision prevalence is between 20-80%, it can be a vital clinical question whether the circumcision should be an option for dealing with UTI. In Asian country, however, there is a sharp division in the prevalence of circumcised males, more than 80% in Islamic countries, South Korea, and Phillipines, but less than 20% in majority of the other countries, including China, India, Japan, and Taiwan [WHO 2007] Because of such radically different cultural background in Asian countries, conclusion lead from studies in one country cannot be equally applied for every Asian countries. At the same time, there are so few literatures from Asian countries on this topic. Consequently, evidences for this chapter are based on nonAsian literatures and its applicability in Asian population is discussed upon socio-cultural context.

Preputial bacterial flora and diagnosis of febrile UTI in boys

Colonization of bacteria in inner prepuce and reduction by circumcision has been documented in many studies^{[81][82][83][84][85][86][87]}. However, there was one article reporting no difference in bacterial culture between circumcised and uncircumcised males^[88], and another article documenting just a modest difference, 37% vs 28% detection of uropathogenic bacteria, between non-circumcised and circumcised patients with VUR under bacterial prophylaxis^[89]. No Asian literature exists in this issue. This aspect should be primarily important upon accuracy in diagnosis of UTI upon urine specimen^[90]. American Academy of Pediatrics advocates in its guideline that urine specimen should be collected by catheterization.

Evidences for circumcision in boys having febrile UTI and/or VUR

With regard to the prevalence of urinary tract infection, there is one prospective randomized study^[91] demonstrating reduction in episodes of febrile UTI but was statistically not-significant. Moreover, there have been cohort studies from Canada^[92], Australia [93], and the United States^[94][95]Shoen et al 2000), a series of epidemiological studies from the United States^{[96][97][98][99]}, 3 meta-analyses, 2 from USA^[100][99] and the other from Australia^[101].　There are also 2 studies comparing incidence of febrile UTI before and after circumcision, one from Turkey^[102], and the other from the United States^[103]. No Asian literature exists in this issue.

There is no prospective study associating circumcision with VUR patients. One cohort study documents that, among boys with VUR detected upon prenatal hydronephrosis, higher rate of breakthrough UTI occurred in non-circumcised boys (53%) than in circumcised boys (19%)^[104].

Another study documents reduced rate of breakthrough UTI after circumcision from 45.2% to 6.2%^[105]. There is one report from Japan^[106]on the incidence of breakthrough UTI during prophylaxis in non-circumcised population. Comparing the two reports, the incidence of breakthrough infection, which was 32.2%, was lower than what was reported in non-circumcised groups, but was higher than in circumcised groups. Another report from Korea discussed the effect of concomitant circumcision with anti-reflux surgery. The authors concluded that circumcision with anti-reflux surgery did not seem to affect the clinical course.^[107] Based on these data, we conclude that circumcision may, but not definitely, reduce the risk of febrile UTI in males.

Other guidelines

Circumcision is described as a therapeutic choice against VUR in AUA guideline 2010. In United States, where circumcision rate varies among races, usually around 70-80%, this choice should be presented to parents. The guideline states that “Although there are insufficient data to evaluate the degree of this increased risk and its duration, parents need to be made aware of this association to permit informed decision-making.”In Europe, the prevalence of circumcision is radically different between countries. Israel and Turkey are at one extreme with nearly 100% prevalence, but less than 20% in majority of other countries. In such context EAU guideline advocates that “Circumcision during early infancy may be considered part of the conservative approach because the procedure has been shown to be effective in reducing the risk of infection in normal children.”.

Phimosis and VUR: An Asian view

In countries where neonatal circumcision is routinely performed, there may exist no clinical problem with regard to this issue. In countries where circumcision is not routinely performed in children, strong objection exists against using this procedure as a treatment of VUR. An opinion leader in eastern Asia, Kenji Shimada presents his view on this issue stating that “ Instead of talking about the negative effect of the prepuce, we have to take lessons from history and reconsider its positive significance.” In such view, countries where circumcision is not performed during childhood (for example China, India, Japan, Taiwan), it is difficult to conceive it as a therapeutic measure both for parents and for physicians. Moreover, the occurrence and treatment of febrile UTI among uncircumcised boys in these countries should be further studied in separate context from the countries where circumcision is highly prevalent.

On the other hand, in countries like Korea and Phillipines where circumcision is performed during childhood, but not as a routine procedure in neonates, one may adopt the conclusions similar to the United States, and may have obligation to present circumcision as a choice of treatment for male infants with febrile UTI and/or VUR. In such countries, setting an appropriate age for circumcision could be an important clinical question, since febrile UTI is more frequent during early infancy.

Labial adhesion and vulvovaginitis

Labial adhesion in its most severe form can block urinary flow and caused retention of urine in the vagina. Vulvovaginitis may be associated with UTI in girls. However, there are few literatures suggesting the involvement of this condition in febrile UTI/VUR.

Diagnosis and management of Risk Factors of UTI: BladderBowel Dysfunction

Summary of Recommendation

Bladder bowel dysfunction encompasses lower urinary tract dysfunction (LUTD) and bowel dysfunction is one of the key factors of progression of renal scarring (LE: 2, GR: A). LUTD can be diagnosed with 4-hours voiding observation in infants and non-invasive urodynamic studies such as uroflowmetry and PVR in toilet trained children (LE: 2, GR: B). Invasive urodynamic studies such as videourodynamic study are reserved for refractory LUTD (LE: 3, GR: C). Bowel dysfunction can be diagnosed with stool form, defecation diary, KUB, and transabdominal ultrasound for rectal distention (LE: 2, GR:B). Early recognition and management of LUTD and bowel dysfunction are important in prevention of UTI recurrence (LE: 2, GR: A).

Diagnosis of LUTD in infants and children

Diagnosis of LUTD in infants can be made with 4-hour voiding observation. Interrupted voiding is defined as re-voiding in 5 minutes. PVR >10ml or 20% bladder capacity may be regarded as elevated PVR. In toilet trained children aged 4-6 years, elevated PVR can be defined as a PVR>20ml or 10% bladder capacity, and in children aged 7-12 years as a PVR >10ml or 6% bladder capacity. Uroflowmetry in toilet trained children is expected to be bell-shaped. Repeat abnormal uroflow pattern is suggestive of LUTD. Details on the differentiation of various type of LUTD are not covered in this paper. Recent studies suggest that infants with a PVR >10ml or 20% bladder capacity was associated with febrile UTI^[108] and children with a PVR higher than the aforementioned age-specific values were at risk of recurrent febrile UTI (Yang 2014).

Significance of LUTD and UTI

LUTD with incomplete bladder emptying is deemed as an important risk factor for development and recurrence of UTI in children^[109]. About 20%-50% of children with UTI and VUR have dysfunctional voiding. (Chen JJ, et al: J Urol 2004;171:1907-1910. Sjostrom S, et al. J Urol 2009;182:2446-54.) Dysfunctional voiding predicts a lower success rate after classical anti-reflux surgery or Deflux® injection. (Higham-Kessler J, et al: J Urol. 2007;177:710-4). Sillen et al reported that infants with LUTD had higher rate of progressive renal scarring than those without LUTD.

Immature voiding pattern, dyscoordination between detrusor and sphincter, is common in infants and frequently subsided after one year of age. Any surgical intervention before one year of age should be carefully considered.

Be havioral modification for LUTD

Clinically, children with UTI and poor fluid intake are encouraged to have more fluid, although relevant studies remain scarce. It is assumed that more fluid intake may result in shorter stasis time of urine in the bladder and better-wash out of bacteria in the bladder. Infrequent voiding, poor fluid intake, functional stool constipation, and dysfunctional voiding were more frequently disclosed in girls with recurrent UTI than in control girls^[110][111]. When managing children with UTI, frequency/volume chart may help physicians and parents monitor the voiding frequency and fluid intake in these children. Elevated PVR has been linked to the development and recurrence of UTI^[109]. Infrequent voiding may result in longer time of bacterial multiplication in the bladder and elevated PVR that was frequently observed in urinary bladder over-distension. Bladder over distension is defined as bladder capacity (voided volume + PVR) larger than 115% expected bladder capacity. At a bladder capacity reaching over-distension, more than one-third of micturition resulted in abnormal uroflow pattern and PVR >20 ml^[112]. Timed voiding schedule is advised in infrequent voiders to decrease the urinary stasis time and to avoid bladder over distension. However, optimal amount of fluid intake is not known. Furthermore, good toilet posture also play a role, which enables optimal relaxation of the pelvic floor muscle and hence reduces dysfunctional voiding and PVR. In postures with adequate bilateral foot support, the relaxation was observed in 94% recorded from the pelvic floor muscles. EMG amplitudes from the pelvic floor and adductor muscles were significantly higher in postures with unsupported legs compared with postures with supported legs^[113].

Biofeedback relaxation of pelvic floor for dysfunctional voiding

Biofeedback relaxation of pelvic floor is helpful in improving voiding symptoms and urodynamic parameters in children with dysfunctional voiding ^[114]. In a study of girls with recurrent UTI underwent a training program including voiding and drinking schedule, pelvic floor relaxation biofeedback, instructions on toilet behavior, and biofeedback uroflowmetry, the program was effective in preventing recurrence of UTI in 35 of 42 (83%) children (De 1998). In a prospective, randomized study comparing pelvic floor exercise and biofeedback therapy in treating children with dysfunctional elimination syndrome, both groups of patients showed low rate of relapsed UTI (3.8% and 10%). Children who received biofeedback therapy had significantly reduced PVR. Children with voiding dysfunction and VUR usually have a high breakthrough infection rate of 34–43%^[115]. Of 37 children with previous history of UTI, VUR and non-neurogenic LUT dysfunction who underwent biofeedback training program only 19% had breakthrough UTI during a mean follow-up of 21 months^[116]. Similarly, breakthrough infection was reduced to 10% after combined conservative medical and computer game assisted pelvic floor muscle retraining program in a mean follow-up period of 24 months^[117].

Diagnosis and management of functional constipation

Constipation is a common problem among children with a prevalence rate ranging from 0.7 to 29.6%^[118]. Rome III criteria defined functional constipation as more than two of the following symptoms: (1) ≦2 defecation/week, (2) >1 fecal incontinence/week, (3) history of retentive posturing or stool retention, (4) painful or hard bowel movements, (5) large fecal mass in the rectum, and (6) large stool obstructing the toilet^[119]. It is postulated that chronic retention of fecal mass above anal verge makes children maintain a high anal sphincter tone. The high anal tone leads to pelvic floor activity and impairs emptying function of bladder and elevated PVR which is an important factor in developing UTI^[120]. This has been confirmed by a recent community investigation of 318 healthy children who had bowel movement ≦2 times/week had higher PVR (9.0 vs. 5.9 ml, P=0.01) and higher chance of elevated PVR (17.7% vs. 7.1%, P=0.01)[Chang 2012]. Another theory is that constipation may increase the uropathogenic organism in the gastrointestinal tract and then may lead to more UTI^[121]. Previous studies have documented correlation between constipation and UTI. Romanczuk et al ^[122] evaluated 180 children suffering from recurrent UTIs and found that treatment of chronic constipation may reduce pyuria, bacteriuria, and enuresis among these children. In a study of 234 children treated for chronic constipation, relief of constipation was obtained in 52% of patients without urinary tract anomaly and resulted in disappearance of UTI^[123]. Koff et al^[124]evaluated 143 children with primary VUR and UTI, 66 had dysfunctional elimination syndrome in which 50% had constipation as the most prominent symptom. Of 66 with dysfunctional elimination syndrome, 82% needed surgical reimplantation of ureter, while only 18% had spontaneous resolution of reflux. Therefore, the importance of managing constipation and voiding dysfunction concurrently can not be overemphasized. Judicious history from parents is as important and well- appreciated information as the Bristol stool form scale in children. A bowel movement diary and a frequency/volume chart should be obtained in children with recurrent UTI and constipation. This allows the physicians and/ or parents to monitor the children’s condition and can supervise them as well.

Treatment of constipation includes osmotic laxatives, stimulant laxatives, increasing fluids intake, biofeedback, and psychological intervention; all are effective in the management of constipation^[125].

Early toilet training

Hellstrom et al.^[126]had empirically suggested early initiation of toilet training in children at risk of developing UTI because children had less bladder sphincter dyssynergia and less post-void residual urine after toilet training^[127][128]. A longitudinal study from Vietnam found that in the children who were potty trained very early, the dyscoordination between bladder and sphincter disappeared at age of 9 months^[126]. A cross sectional study disclosed that the rate of abnormal voiding function was comparable between toilet training before and after 18 months of age^[129].

Late toilet training may result in higher rates of lower urinary tract symptoms. A cohort study in the UK showed that initiating toilet training after 24 months was associated with problems attaining and maintaining bladder control^[130]. However, there is a lack of prospective randomized studies to confirm the efficacy of early toilet training in reducing episode of recurrent UTIs.

Diagnosis and management of Risk Factors of UTI: VUR

Summary of Recommendation

1. At initial presentation the child with VUR should undergo a careful general medical evaluation including measurement of height, weight and blood pressure, as well as serum creatinine if bilateral renal cortical abnormalities are found (LE:2, GR: A).

2. Because VUR and UTI may affect renal structure and function, performing renal ultrasound to assess the upper urinary tract is recommended (LE: 2, GR: B).

3. DMSA renal imaging can be obtained to assess the status of the kidneys for scarring and function (LE: 1, GR: B).

4. VCUG is indicated when abnormalities are apparent on either renal/bladder ultrasound or DMSA scan or both (LE: 2, GR: B). VCUG is also suggested after a repeat febrile UTI (LE: 2, GR: B).

5. Despite the concerns about ionizing radiation and its invasive nature, conventional VCUG remains the gold standard because the test allows better determination of the grade of VUR (in a single or duplicated kidney) and better assessment of bladder and urethral configuration (LE: 2,GR: B).

6. Antibiotic prophylaxis to prevent recurrent febrile UTI is indicated in children with moderate to high grade (III-V) VUR (LE: 1b, GR: A).

7. Surgical intervention should be used to treat VUR in the setting of recurrent febrile UTI because it has been shown to decrease the incidence of recurrent pyelonephritis (LE: 1b, GR: A).

8. Bladder dysfunction increases the risk of urinary tract infections and can lead to significant delay in spontaneous resolution of VUR. Its detection by careful history and its efficient treatment therefore is mandatory in affected children (LE: 2, GR: B).

Introduction

A significant percentage of febrile UTIs are associated with VUR, especially in children evaluated before toilet training.^[131] While VUR may be a benign condition with few long-term sequelae, it may also produce end stage renal disease. The rationale for prompt diagnosis and proper treatment of VUR in children with febrile UTIs are the prevention of recurrent pyelonephritis and its potential consequences, such as renal scarring. This is especially the case for younger child with “immature” kidneys that have been considered at increased risk for acquired renal scarring secondary to pyelonephritis. 2 (Olbing et al, 2008) This section will focus on the diagnosis and evaluation of VUR as one of risk factors of UTI in children.

Diagnostic work-up for VUR in children with febrile urinary tract infection

In children with febrile UTI the diagnostic work-up should be focused on the evaluation of the health and development of the child, renal status, presence of VUR, and lower urinary tract function. This includes a detailed medical history (e.g. family history and screening for LUTD), a physical examination including blood pressure measurement, urinalysis (assessing for proteinuria), urine culture as indicated, and measurement of serum creatinine level in patients with bilateral renal parenchymal abnormalities. The standard imaging tests include renal and bladder ultrasonography, dimercaptosuccinic acid (DMSA) renal scan, and voiding cystourethrography(VCUG).

The standard criterion for the diagnosis of VUR is detection on VCUG. Traditionally, VCUG has been recommended in children with first proven febrile UTI. Radionuclide cystography for the detection of reflux have lower radiation exposure than conventional VCUG, but the anatomic detail depicted is inferior.4^[132] Radionuclide cystography is useful for follow up. Recent studies on alternative imaging modalities for the detection of VUR have yielded good results with voiding urosonography and magnetic resonance VCUG.5-7^{[133][134][135]} However, despite the concerns about ionizing radiation and its invasive nature, conventional VCUG remains the gold standard because the test allows better determination of the grade of VUR (in a single or duplicated kidney) and better assessment of bladder and urethral configuration. If reflux is diagnosed on VCUG, further evaluation traditionally consists of a DMSA renal scan (“bottom-up” approach).

DMSA is the best nuclear agent for visualizing the cortical tissue and differential function between both kidneys. DMSA scan is used to detect and monitor renal scarring. A baseline DMSA scan at the time of diagnosis can be used for comparison with successive scans during follow-up.^[136][137] Recently an alternative “top-down” approach is more recommended. This approach carries out a DMSA scan first, close to the time of a febrile UTI, to determine the presence of pyelonephritis, which is then followed by VCUG if the DMSA scan reveals kidney involvement. A normal DMSA scan with no subsequent VCUG will fail to detect VUR in 5–27% of cases, with the cases of missed VUR being presumably less significant. In contrast, a normal DMSA scan with no VCUG will avoid unnecessary VCUG in over 50% of individuals screened.^{[138][139][140][141]} Video urodynamic studies are important only in patients in whom secondary reflux is suspected, such as patients with spina bifida, and in boys with a diagnosis of posterior urethral valves, for whom bladder dynamics necessitate regular follow-up.

Screening of asymptomatic siblings of reflux patients

The screening of asymptomatic siblings of reflux patients is controversial. Some authors think that early identification of children with VUR may prevent episodes of UTI and therefore renal scarring, while others think that screening asymptomatic individuals is likely to result in significant overtreatment of clinically insignificant VUR. The estimate for renal cortical abnormalities is 19.3% (range: 11–54%), with 27.8% of patients in cohorts of symptomatic and asymptomatic children combined having renal damage. In asymptomatic siblings only, the rate of renal damage is 14.4% (range: 0–100%). Early screening appears to be more effective than late screening in preventing further renal damage by early diagnosis and treatment.^{[142][143][144][145]} The lack of randomized clinical trials for screened patients to assess clinical health outcomes makes evidence-based guideline recommendations for VUR screening difficult.

Importance of Low Urinary Tract Dysfunction in VUR VUR, UTI and LUTD are frequently associated.^{[61][146][147]} About half of children with VUR have bladder dysfunction.20^[57]Bladder function influences the spontaneous regression rate of reflux.^{[124][147][148][149]} These observations support the current view that bladder function is an important predictive parameter for spontaneous reflux resolution, susceptibility for pyelonephritic episodes and for renal damaging.

This awareness has implications for conservative reflux therapy. It must include the treatment of pre-existing bladder dysfunction to be successful in the long run.^[150]

Breast milk, cranberry products, probiotics and other means to prevent UTI

Summary of Recommendation

1. Breast feeding may protect infants from UTI (LE: 2), and is strongly recommended for prevention of UTI in infants (GR: A).

2. Cranberry and related products may prevent UTI in children (LE: 3) and may be considered in the prevention of UTI in children (GR: C).

3. Probiotics may prevent UTI in children and in children (LE: 3) and may be considered in the prevention of UTI in children (GR: C).

Breast milk

The protective role of breast milk may be attributed to the specific contents within the breast milk, including immunoglobulin A^[151], anti-adhesive oligosaccharide^[152], and lactoferrin^[151]. The antibacterial effect and selection of low uropathogenic bacteria play the role. Marid et al. observed that shorter duration of breastfeeding was associated with higher risk of UTI in children^[153]. Recently, the same group concluded that ongoing breastfeeding and a longer duration of breastfeeding resulted in a lower risk of infection after weaning, especially in girls^[154]. The protective role of breastfeeding was strongest directly after birth; then, it decreased after 7 months of age. Recently, a case–control study enrolled 6198 premature infants and showed that breast milk is associated with lower risk of getting UTIs (OR = 0.314, 95% CI 0.140–0.707)^[155]. In addition to UTI, breast feeding also reduced the risk of acute respiratory infections, acute otitis media, and thrush in the first 6 months of life^[156]. Since breast feeding has many benefits and bears no risk, we strongly recommended breastfeeding to prevent recurrence of UTI in children with one episode of UTI.

Cranberry

From a meta-analysis by Jepson and Craig, there is some evidence supporting the use of cranberry in reduction of UTI episodes among women with recurrent UTI, while there is scarce randomized trial evaluating the effectiveness of cranberry in children^[157]. The evidence of the role of cranberry in prevention of UTI in children was still inconclusive, although cranberry juice consumption provides significant anti-adherence activity against different E. coli uropathogenic strains in the urine compared with placebo^[158]. Schlager et al conducted a double-blind, placebo-controlled, crossover study to determine the effect of cranberry juice on pyuria and symptomatic UTI in children with neurogenic bladder needing clean intermittent catheterization^[159]. They found that cranberry concentrate had no effect on bacteriuria in the study population, although this may be partly due to host susceptibility to infection. Foda et al conducted a randomized single-blind cross-over study to compare cranberry juice and water, and no difference in infection of the intervention periods was observed^[160]. Ferrata et al enrolled 84 girls with E. coli urinary tract infections^[161]. They were randomized to receive cranberry, lactobacillus, and control group. Girls who received daily cranberry juices had less recurrence rate of UTIs. Another study showed that cranberry juice had comparable effects with cofactor in preventing UTIs in children with vesico-ureteral reflux^[162]. Studies mentioned above only enrolled small number of children; more studies are required to elucidate the role of cranberry in prevention of pediatric UTI.

Probiotics

The term probiotics is defined as ‘‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’’ ^[163]. The concept of probiotics developed from normal flora that existed in the gastrointestinal tract and genital area. The introduction of probiotics in the prevention of recurrent UTI was largely due to antibiotics failure and increased evidence of the efficacy of probiotics^[163]. However, controversy exists over the efficacy of probiotics in prevention of pediatric UTI. Dani et al.^[164]administered Lactobacillus GG in neonates with UTI, sepsis, and necrotizing enterocolitis; no significant effect of Lactobacillus GG in reduction of UTI was noted. Two prospective, randomized controlled studies compared the conventional antibiotics and probiotics in treating children and infants with primary VUR; the incidence of recurrent UTI was comparable in both groups of children^[165][166]. Long-term effects of probiotics in children need further evaluation. Also, which strains of lactobacillus are more helpful in preventing pediatric UTI needs further elucidation. Despite the possible clinical effects of probiotics on UTI in children, 2 cases with bacteremia of lactobacilli were reported^[167].

Acknowledgement: The authors would like to thank Dr. Fluorence M. Flores for English editing.

Abbreviations

BBD: Bladder bowel dysfunction, CI: Confidence interval, DMSA: Technetium-99m-labeled dimercaptosuccinic acid, GR:: Grade of recommendation, LE:: Level of evidence, LUTD: Lower urinary tract dysfunction, RCT: Randomized control study, RR: Relative risk, UTI: Urinary tract infection, VUR: Vesicoureteral reflux, VCUG: voiding cystourethrography

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