ITU Children

Vol. 64 - No. 2 MINERVA PEDIATRICA 145

der are generally accompanied by localized symptoms and are easily treated. In contrast, the presence of fever increases the proba-bility of kidney involvement (53-84% sensi-tivity, 44-92% specificity) 3 and is associated with an increased likelihood of underlying nephrourologic abnormalities and a greater risk of consequent renal scarring,4 support-ing the concept that delays in the institution of antibiotic treatment of pyelonephritis in-crease the risk of renal damage.5, 6

Since recently, kidney scarring related to UTI has been considered a cause of sub-stantial long-term morbidity.7 Thus, children with proven infections have been inten-sively evaluated and treated, and they have often undergone surgery or have received long-term antibiotic prophylaxis.3, 7-12 These approaches,13, 14 especially voiding cys-tourethrography (VCUG) 15-22 and the use of antibiotic prophylaxis 23-26 have been re-cently questioned.

One of these studies showed a high prev-alence of scarring (38%) before treatment was started, whereas rates of new scarring and progression of existing scarring were low (2% and 9%, respectively) and were unrelated to persistent reflux or break-through infections.11 Such results highlight an important issue: the distinction between

Sacro Cuore Catholic University, Rome, Italy

MINERVA PEDIATR 2012;64:145-57

D. BUONSENSO, L. CATALDI

Urinary tract infections in children: a review

Febrile urinary tract infection is the most common serious bacterial infection in child-hood, but the most appropriate evaluation of children with this condition is still unclear, overall regarding the best long-term manage-ment of children after a first UTI. Here we re-view current recommendations for the diag-nosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection. Neverthe-less, the development of a universally accept-ed diagnostic protocol remains elusive.Key words: Urinary tract infections - Child - Ultrasonography.

Acute pyelonephritis is the most com-mon serious bacterial infection in child-

hood. About 7 to 8% of girls and 2% of boys have a urinary tract infection (UTI) during the first 8 years of life.1, 2 Febrile UTIs have the highest incidence during the first year of life in both sexes, whereas nonfebrile UTIs occur predominantly in girls older than 3 years.2

Establishing the diagnosis is difficult in early childhood due to the absence of spe-cific symptoms, and difficulty in collection of not contaminated urine samples without invasive methods (urethral catheterization or suprapubic aspiration [SPA]).

After infancy, UTIs confined to the blad-

Corresponding author: D. Buonsenso, Department of Pediatrics Catholic University of the Sacred Heart, L.go A. Gemelli 8, 00168 Rome, Italy. E-mail: [email protected]

Anno: 2012Mese: AprilVolume: 64No: 2Rivista: MINERVA PEDIATRICACod Rivista: MINERVA PEDIATR

Lavoro: titolo breve: URINARY TRACT INFECTIONS IN CHILDRENprimo autore: BUONSENSOpagine: 145-57

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146 MINERVA PEDIATRICA April 2012

BUONSENSO URINARY TRACT INFECTIONS IN CHILDREN

primary renal damage that precedes infec-tion and scars related to UTI. Primary renal damage is linked to prior obstruction, ge-netic and developmental factors that result in maldevelopment (hypodysplasia) of the urinary tract, or both. However, inflamma-tory processes (pyelonephritis) that occur in the context of infection may also pro-duce scars.27

In 2007, the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) 28 published new guidelines for the management of UTI in children, which rec-ommend more selective

use of renal ultrasonography (US) and VCUG. Similarly, the 2011 American Acade-my of Pediatrics guidelines 29 do not recom-mend routine use of imaging techniques.

This new attitude could be of particular interest, since current imaging, prophylaxis, and prolonged follow-up strategies place a heavy burden on patients, families, and national health systems resources and carry risks without evidence of benefit.

Methods

This review focuses on pathophysiology, diagnosis and management of initial UTIs in febrile infants and young children who have no obvious neurologic or anatomic abnormalities known to be associated with recurrent UTI or renal damage. Following results cannot be generalized to newborns and infants less than 2 months of age, since there are special considerations in this age group to be considered and that limit the applicability of evidences derived from studies of older children.

Pathophysiology of febrile UTI

Acute pyelonephritis occurs when bacte-ria ascend to the kidneys and cause intra-renal infection. Escherichia coli bacteria are characterized by the presence of P fimbri-ae which permit them to attach to uroepi-thelial cells and to not be flushed out by urine flow. The endotoxin (lipopolysaccha-

ride) of the bacteria binds to CD14 on the cell surface, activating toll-like receptor 4. Through a different complex and not yet completely understood steps, this activates transcription factor nuclear factor κB (NF-κB), which migrates into the cell nucleus, stimulating production of inflammatory fac-tors, including cytokines, chemokines, ni-tric oxide, and transforming growth factor β. These mediators induce an inflammatory response, which increases vascular perme-ability, recruitment of neutrophils and re-lease of mediators that on one hand help to resolve the infection (with the help of antimicrobial agents), on the other hand are also responsible in part for the ensuing kid-ney scarring.27

When to suspect a UTI?

NICE guidelines 29 highlight the need of considering a diagnosis of UTI in all in-fants and children with unexplained fever of 38 °C or higher after 24 hours at the lat-est, and in children having symptoms and signs suggestive of UTI, including fever and non-specific symptoms, such as lethargy, ir-ritability, malaise, failure to thrive, vomiting, poor feeding, abdominal pain, jaundice (or having more specific symptoms particularly in older children - such as frequency, dysu-ria, loin tenderness, dysfunctional voiding, changes to continence, hematuria, and of-fensive or cloudy urine).28

Similarly, the AAP 2011 guidelines 29 state that a clinician should consider a UTI when-ever he thinks that a febrile infant with no apparent source of infection requires an-tibiotic therapy because of ill appearance. Moreover, the AAP 2011 guidelines encour-age the doctor to determine the risk that a particular child has to have a UTI during a febrile episode (Table I).

How to diagnose a UTI?

The clinician should ensure that a urine specimen is obtained for both culture and urinalysis before an antimicrobial agent is

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URINARY TRACT INFECTIONS IN CHILDREN BUONSENSO

the test. Table II describes characteristics of urinalysis tests.

To establish the diagnosis of UTI, clini-cians should require both urinalysis results that suggest infection (pyuria and/or bacte-riuria) and the presence of at least 50 000 colony-forming units (CFUs) per mL of a uropathogen cultured from a urine specimen obtained through catheterization or SPA.

When should a child be hospitalized?

Hospital admission is indicated in the fol-lowing situations:37

— neonates and infants younger than 3 months;

— severely ill children (sepsis, dehydra-tion, vomiting);

— concern of noncompliance; — fever persisting after 3 days of appro-

administered; the specimen needs to be ob-tained through catheterization (95% sensi-tivity, 99% specificity) 30-32 or SPA, because the diagnosis of UTI cannot be established reliably through culture of urine collected in a bag (up to 88% of false-positive results, ≈68% specificity).33-35 The techniques re-quired for catheterization and SPA are well described.36

Urinalysis cannot substitute for urine culture to document the presence of UTI but needs to be used in conjunction with culture, since urine culture results are not available for at least 24 hours.

Urinalysis can be performed on any specimen, including one collected from a bag applied to the perineum. However, the specimen must be fresh (<1 hour after void-ing with maintenance at room temperature or <4 hours after voiding with refrigera-tion), to ensure sensitivity and specificity of

Table I.—�UTI probability among febrile boys and girls.

Probability of UTI N. of factors present (girls) (31)

N. of factors present (uncircumcised boys) (32)

N. of factors present (circumcised boys) (32)

≤ 1% ≤ 1 Always >1% even with no risk factors other than being uncircumcised

≤ 2

≤ 2% No more than 2 None No more than 3

— Risk factors for girls: white race; age <12months; temperature ≥ 39°C; fever lasting more than 2 days; absence of another source of infection.— Risk factors for boys: nonblack race; temperature ≥ 39°C; fever lasting more than 24 hours; absence of another source of infection.Adapted from AAP guidelines 2011.29

Table II.—�Characteristics of urinalysis components.

Test Comments Sensitivity % (range) Specificity % (range)

Nitrite test little value in ruling out UTI (not all urinary patho-gens reduce nitrate to nitrite); helpful when positive (highly specific)

53 (15–82) 98 (90–100)

Leukocyte esterase testit distinguishesindividuals with asymptomatic bacteriuria (absence of leukocyte esterase in the urine) from those with true UTI.

83 (67–94) 78 (64–92)

Microscopy, WBCs The absence of pyuria in children with true UTIs is rareWBCs may be found in the urine during other con-ditions (eg, streptococcal infections or Kawasaki disease), and after vigorous exercise.The key to distinguishing true UTI from asympto-matic bacteriuria is the presence of pyuria.

73 (32–100) 81 (45–98)

Microscopy, bacteria 81 (16–99) 83 (11–100)

Adapted from AAP guidelines 2011.29

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Children should be treated for 7 to 14 days.27-29

Cephalosporins and amoxicillin/clavu-lanate are the most used oral antibiotics. When intravenous treatment is required, no particular antibiotic has been shown to be superior; cephalosporins and aminoglyco-sides are frequently recommended.45, 46

Table III lists the main characteristics of commonly used antibiotics for febrile UTI.

What to do after a first febrile UTI?

Prophylaxis

For the past 4 decades, continuous an-timicrobial administration as prophylaxis aimed to protect the kidneys from further damage after an initial UTI in children with genitourinary abnormalities was the main-stay of the management of UTI, since recur-rent UTIs were considered to increase renal damage.29

However, since there is a significant number of infants in whom vescico-ureteral reflux (VUR) cannot be demonstrated who develop pyelonephritis, the effectiveness of antimicrobial prophylaxis has been chal-lenged in the past decade. Several stud-ies have suggested that prophylaxis does not confer the desired benefit of prevent-ing recurrent febrile UTI.24-26 A χ2 analysis (2-tailed) and a formal meta-analysis of these studies did not detect a statistically significant benefit of prophylaxis in pre-venting recurrence of febrile UTI/pyelone-phritis in infants without reflux or those with grades I, II, III, or IV VUR.29 Because only 5 infants with grade V VUR were in-cluded in these studies, this statement can-not be used for children with grade V VUR until randomized controlled trials (RCTs) will be conducted with this population.29 In fact, prompt diagnosis and effective treat-ment of a febrile UTI recurrence (see Table IV for the definition of recurrence) may be of greater importance regardless of wheth-er VUR is present or the child is receiving antimicrobial prophylaxis. Therefore, cur-rent AAP guidelines state that antimicrobial

priate antibiotic treatment as shown by the sensitivity testing.

How to treat a UTI?

The goals of treatment of acute UTI are to eliminate the acute infection, to prevent complications, and to reduce the likelihood of renal damage. The majority of children can be treated orally.38-40 Patients who ap-pears to be “toxic” or are unable to retain oral intake should be treated parentally un-til they exhibit clinical improvement, usu-ally within 24 to 48 hours, and are able to retain orally administered fluids and medi-cations.29

Only antimicrobials that reach high blood concentrations should be used to treat fe-brile infants with

UTIs, because parenchymal and serum antimicrobial concentrations may be insuf-ficient to treat pyelonephritis or urosepsis when using agents that are excreted in the urine but do not achieve therapeutic con-centrations in the bloodstream.27

The antimicrobial agent should be cho-sen based on local antimicrobial sensitivity patterns (if available) and the choice should be re-evaluated according to sensitivity test-ing of the isolated uropathogen.29 This con-cept is of primary importance, since antibi-otic resistance is a growing concern.41 The rate of isolated E. coli (the most common organism isolated,19 accounting for up to 80% of infections) resistant to first-line anti-biotics such as ampicillin and trimethoprim/sulfamethoxazole is constantly increasing.42,

43 Chakupurakal et al.44 have found in the United Kingdom that E. coli UTIs were uniformly susceptible to amoxicillin/cla-vulanate in 2002, but the resistant pattern changed in 2008, with 48% of E. coli UTIs being resistant.41

Even though a recent Belgium prospec-tive study 41 involving 209 children treated for first febrile UTI found an 8% resistance rate to amoxicillin/clavulanate, the concern of antibiotic resistance should always be taken into consideration in daily clinical practice.

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Table III.—�Main characteristics of commonly used antibiotics for febrile UTI.

Antimicrobial agent

Dosage (parenteral treatment)

Dosage (oral treatment) Pharmacokinetics 47 Pharmacodnamic 47 Comments 27, 47

Amoxicillin-clavulanate

20–40 mg/kg per d in 3 doses (30)45 mg per kg twice per day (dose ex-pressedin amoxicillin-equiva-lent units)

Half-life: 1.5hMetabolism: hepaticExcretion: urineDistribution: widely distributed (except CNS)

inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. Ad-dition of clavulanate inhibits beta-lactamase producing bacteria

Increasing resistance

Trimethoprim-sulfamethox-azole

6–12 mg/kg trimetho-prim and 30-60 mg/kg sulfamethoxazoleper d in 2 doses (30)4 mg per kg twice per day (dose expressed intrimethoprim-equivalent units)

Half-life: TMP 8-10h, SMX 10-12hMetabolism: liverExcretion: urineEnzymes inhibited: hepatic CYP2C9

TMP Inhibits dihydro-folate reductase; SMX competes with para-aminobenzoic acid

High resistance rates; risk of allergic reaction

Ceftriaxone 75 mg/kg, every 24 h

Half life: 8 hoursAbsorptionIM: well absorbedDistributionWidely throughout the body including gall-bladder, lungs, bone, bile, CSF (higher con-centrations achieved when meninges are inflamed); crosses pla-centa; enters amniotic fluid and breast milkMetabolism: liverExcretion: urine (33-65% as unchanged drug), the remainder secreted in bile and ultimately in feces as microbiologically inac-tive compounds.

Third-generation cephalosporin with broad-spectrum, Gram- activity; lower efficacy against Gram+ organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin bind-ing proteins. Exerts antimicrobial effect by interfering with syn-thesis of peptidogly-can, a major structural component of bacte-rial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is ar-rested.

Advantage of once-daily dosing; contrain-dicatedin neonates, especially premature infants;increasing resistance (for all cephalosporins)

Cefotaxime 150 mg/kg per d,divided every 6–8 h

Half-life: 1-1.5hDistributionWidely throughout the bodyMetabolism: partially in liver to active me-tabolite desacetylcefo-taximeExcretion: urine

Penicillin-binding proteins

3rd generation cepha-losporin

Ceftazidime 100–150 mg/kg per d,divided every 8 h

Metabolism: partial, hepaticExcretion: urine

Arrest bacterial growth by binding to one or more penicillin-bind-ing proteins, which, in turn, inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall synthesis, thus inhibiting cell wall biosynthesis

3rd generation cepha-losporinGood coverage for pseudomonas

Cefixime 8 mg/kg per d in 1 dose

Half-life: 0.8-1.3hExcretion: unchanged in urine (80-100%)

Penicillin-binding proteins

1st generation cepha-losporin

Cephalexin 50–100 mg/kg per d in 4 doses

Half-life: 0.8-1.3hExcretion: unchanged in urine (80-100%)

1st generation cepha-losporin

(Continue)

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Table III.—�Main characteristics of commonly used antibiotics for febrile UTI.

Antimicrobial agent

Dosage (parenteral treatment)

Dosage (oral treatment) Pharmacokinetics 47 Pharmacodnamic 47 Comments 27, 47

Cefpodoxime 10 mg/kg per d in 2 doses

Half-life: 2-3h (pro-longed with renal impairment)Absorption: oral 50%, acid stableMetabolism: liver, to active metaboliteExcretion: unchanged in urine 80%

Binds to one or more of the penicillin-binding proteins; bac-teria eventually lyse because of ongoing activity of cell wall au-tolytic enzymes while cell wall assembly is arrested

3rd generation cepha-losporin

Cefprozil 30 mg/kg per d in 2 doses

Half-life: 1.3hAbsorption: oral 94%Metabolism: liverExcretion: urine 61% unchanged

Binds to one or more of the penicillin-bind-ing proteins, which in turn inhibits cell wall synthesis and results in bactericidal activity.

2nd generation cepha-losporinHas Gram+ activity that 1st generation have and adds activity against P mirabilis, H influenza, E coli, K pneumonia and M catarrhalis

Cefuroxime axetil

20–30 mg/kg per d in 2 doses

Half-life: 1-2hAbsorption increased with foodMetabolism: liver partiallyExcretion: urine 66-100% unchanged

Binds to penicil-lin binding proteins and inhibits final transpeptidation step of peptidoglican synthesis; resists degradation by beta-lactamase.

2nd generation cepha-losporin

Gentamicin 7.5 mg/kg per d,divided every 8 h

Half-life: 2-3 hoursExcretion: urine as unchanged drugClearence: directly re-lated to renal funtion

Interferes with bacte-rial protein synthesis by binding to 30S and 50S ribosomal subunits

Useful for patients with cephalosporin allergy;nephrotoxic; serum levels must be moni-toredand dosage adjusted accordingly; single dailydosage supported by meta-analysis 55

Tobramycin 5 mg/kg per d,divided every 8 h

Half-life: 2-3 hoursExcretion: urine within 24h in normal renal funtion

binds to 30S and 50S ribosomal subunits

Amikacin 7.5 mg per kg twice per day

Half-life: 2-3 hoursEliminated renally.Administered IV over 30-60 min.Distribution:Primiraly into extracelllular fluid (highly hydrophilic); penetrates blood-brain barrier when menin-ges inflamed.

Irreversibly binds to 30S subunit of bacte-rial ribosomes; blocks recegnition step in protein synthesis; causes growth inhibi-tion. For Gram- bac-terial coverage of infections resistant to gentamicin and tobramycin.

Piperacillin - tazobactam

2–9 months of age: 80 mg of piperacillin and 10 mgof tazobactam per kg three times per day; morethan 9 months of age: 100 mg of piperacillin and12.5 mg of tazobactam per kg three times per day

Half-life: 1h, metabo-lites 1-1.5h.Metabolism: hepaticExcretion:Piperacillin 68% urin, tazobactam 80% urine, both also in bile

Anti-pseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wass mucopep-tide and is effective during stage of active multiplication

Broad spectrum of bactericidal activity

Ciprofloxacin 10–20 mg per kg twice per day

Half-life: 4-6 hExcretion: urine (25-65%), feces (20-40%)Enzymes inhibited: hepatic CYP1A2

Inhibits relaxation of DNA; inhibits DNA-gyrase in susceptible organisms; promotes breakage of double-stranded DNA

A second choice for the treatment of com-plicatedurinary tract infections; increasing resistance;increased risk of mus-culoskeletal adverse events

(Continues from previous page)

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ics utilised in the literature, but their resist-ance rate is increasing.

The Randomized Intervention for Children With Vesicoureteral Reflux study (RIVUR; ClinicalTrials.gov number, NCT00405704) which is enrolling 600 children 2 to 72 months of age with grade I to IV vesi-coureteral reflux after an index febrile or symptomatic UTI, will probably provide valuable information.51

Adjunctive treatments

Cranberry juice, which is considered to inhibit bacterial adhesion to uroepithelial cells,27 has been used for the prevention of recurrent UTIs 52 and its effectiveness in decreasing the number of symptomatic UTIs in women 53 and children 54 has been shown.

Circumcision has also been shown to be associated with a reduced risk of UTI,55 but it would provide a net clinical benefit only in boys at high risk for UTI or in those with high-grade reflux.27, 56

Surgical management

VUR can be corrected either by surgical reimplantation of the ureter or endoscopic injection of a bulking agent next to the vesi-coureteral junction, with a reported resolu-tion rate of 98.1% for open surgery (95% CI, 95.1 to 99.1) and 83.0% for endoscopic ther-apy (95% CI, 69.1 to 91.4) after a single in-jection.27, 57 Nevertheless, the American Uro-logical Association guidelines 57 recommend antibiotic prophylaxis rather than surgery for all infants with VUR but children with higher reflux grades and the presence of scarring.

AAP 29 and NICE 28 guidelines do not dis-cuss the surgical management of UTIs.

prophylaxis is not as effective as previously thought. Similarly, NICE guidelines suggest to not prescribe antibiotic prophylaxis rou-tinely.28

Nevertheless, a large trial involving 576 children demonstrates a modest favorable effect on the recurrence of both sympto-matic and febrile UTIs.48 A more recent RCT (203 children) shows favorable effects on recurrence of infections, especially in girls >1 year old, with reflux grade III and IV.49 There was no benefit in boys from any of the treatments in that study. An increased bacterial resistance to the pro-phylactic drug has been described in these studies.

Montini et al.27 in a recently published re-view highlight that the role of prophylaxis is questionable in children with no reflux or with grade I or II reflux, given a recurrence rate for infection of 3 to 8% per year with-out prophylaxis.42 For children with grade III to V reflux, who have a much higher rate of reinfection (28% to 37%) 42, 49 prophy-laxis would seem appropriate, particularly in girls.

According to the latest Italian Guidelines on the management of UTI in children, an-tibiotic prophylaxis 50 should not be recom-mended routinely in infants and children after the first UTI.

It has to be considered in infants and children:

a. after the treatment of the acute epi-sode until cystography is performed;

b. with reflux grade >III;c. with recurrent febrile UTIs (>3 febrile

UTIs within 12 months).The optimal duration of antibiotic proph-

ylaxis is not well established; we suggest 1 to 2 years. Amoxicillin-clavulanate and cot-rimoxazole are the most common antibiot-

Table IV.—�Definition of recurrent UTI.

Consider a UTI as recurrent with any of the following – Two or more episodes of UTI with acute pyelonephritis or upper UTI – One episode of UTI with acute pyelonephritis or upper UTI plus one or more episode of UTI with cystitis or lower urinary tract infection

– Three or more episodes of UTI with cystitis or lower UTI

Adapted from NICE guidelines.28

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The AAP 29 suggests a different timing of RBUS according to the clinical situation. RBUS is recommended during the first 2 days of treatment when the clinical illness is unusually severe or there is no evident clin-ical improvement, in order to identify seri-ous complications such as renal or perirenal abscesses or pyonephrosis associated with obstructive uropathy. For febrile infants with UTIs who clearly demonstrate clinical improvement imaging does not need to oc-cur early during the acute infection and can even be misleading.

NICE guidelines 28 suggest to perform RBUS of the urinary tract during the acute infection only in children of all ages with atypical UTI (see Table V for definition), while suggest to perform RBUS within six weeks of the infection in infants younger than 6 months with first time UTI that is responsive to treatment.

According to Montini et al.,27 after an un-complicated first febrile UTI in a child under 3 years of age, the first step is to ascertain whether a reliable, normal ultrasonographic study performed during the third trimester of pregnancy is available for review; if not, RBUS could be performed. If the course of a UTI is atypical, RBUS is indicated (agree-ing with NICE guidelines).

Imaging: VCUG

VCUG should not be performed routinely after the first febrile UTI; VCUG is indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clini-cal circumstances.28, 29 If prophylaxis is, as already mentioned, not beneficial and VUR is not required for development of pyelone-phritis, then the rationale for performing VCUG routinely after an initial febrile UTI must be questioned.

The NICE algorithm for imaging studies in children with UTI is shown in Table VI.

The validity of the NICE algorithm has been recently highlighted by a retrospec-tive review 64 comparing outcomes during periods before algorithm use (September

Imaging: renal and bladder ultrasonogra-phy (RBUS)

The best approach to evaluating a child after a first febrile UTI is still an enormous issue.

AAP 2011 guidelines 29 state that febrile infants with UTIs should undergo RBUS in order to detect anatomic abnormalities that require further evaluation, such as ad-ditional imaging or urologic consultation and to provide an evaluation of the renal parenchyma and an assessment of renal size that can be used to monitor renal growth.

The rate of ultrasonographic detection of grade III to V reflux ranges from 22%, when only dilatation of the urinary tract is defined as abnormal,22 to 67% 58 and 86%,59 when other ultrasonographic abnormalities (renal hypodysplasia, thickened bladder or pelvis wall, or signs of pyelonephritis) are includ-ed.27 Nevertheless, this imaging technique does not reliably detect low-grade reflux, pyelonephritis, or scarring.22 In three trials involving a total of 864 children, prospec-tive US after an initial febrile UTI failed to reliably detect changes associated with re-flux or subsequent renal damage 24, 60, 61 and had little influence on subsequent manage-ment. A systematic review 62 and a more recent study 63 indicated that approximately 70% of renal and urinary tract anomalies are already detected antenatally by means of routine US performed during the second and third trimesters of pregnancy, but the consequences of prenatal screening with respect to the risk of renal abnormalities in infants with UTIs have not yet been well defined.29

Table V.—�Definition of atypical UTI.

Consider a UTI as atypical with any of the following – Septicaemia or seriously ill children – Poor urine flow – Abdominal or bladder mass – Raised creatinine concentration – Failure to respond to adequate treatment within 48 hours

– Infection with an organism other than E. coli

Adapted from NICE guidelines.28

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Imaging: renal scintigraphy

Renal scintigraphy with 99mTc-dimer-captosuccinic acid (DMSA) performed dur-ing the acute phase of a UTI, followed by VCUG if the scintigraphic examination sug-gests pyelonephritis (once a urine culture is negative), has been referred to as the “top down” approach 65, 66 and focuses on pu-tative pyelonephritis and scarring. This ap-proach may decrease the number of VCUG examinations performed.

Some expertise recommend renal scin-tigraphy 6 to 12 months after an acute in-fection to detect the formation of scarring, which would require follow-up.61, 67 In particular, Zaffanello et al.68 prospectively evaluated children who had experienced the first febrile UTI at or under the age of 2 years with normal fetal routine ultrasound. All the children underwent renal ultrasound after admission; those with sonographic signs of obstruction were excluded. VCUG and DMSA scintigraphy were performed approximately 1 month and 6 months after the UTI, respectively. VUR was detected in 55.4% of the children and renal scarring in 18.5%. The severity of VUR correlated sig-nificantly with renal scarring. The authors concluded that follow-up renal scintigra-phy 6 months after a UTI can predict se-vere VUR in very young children showing renal scarring, detecting only those who are

1, 2006, to August 31, 2007) and after al-gorithm use (September 1, 2008, to August 31, 2009). Schroeder et al noted a dramatic reduction in VCUGs following a febrile UTI under the selective algorithm from 99% down to 13% and a lesser but still signifi-cant decrease in RBUS (from 99% to 67%). They demonstrated no significant differ-ence in cases of grades 4 and 5 VUR identi-fied. A reduction in antibiotic prophylaxis from 27% to 3%, primarily due to lack of detection of lesser grades of VUR, was not associated with an increased incidence of recurrent UTI. The authors concluded that by restricting urinary tract imaging after an initial febrile UTI, rates of VCUG and prophylactic antibiotic use decreased sub-stantially without increasing the risk of UTI recurrence within 6 months and without an apparent decrease in detection of high-grade VUR.

This selective approach reduces the cost and distress associated with the pro-cedure (which necessitates instillation of a radiopaque, radioactive, or echocontrast medium into the bladder through urethral catheterization, followed by serial imaging during filling and voiding) in children with an uncomplicated first febrile UTI who are otherwise well. However, the selective ap-proach may miss a number of children who have clinically important reflux until anoth-er infection occurs.16, 27, 28

Table VI.—�The NICE algorithm for imaging studies after febrile UTIs.28

Study Responds well to therapy by 48 hNot atypical or recurrent UTI Atypical UTI History of

prior UTI

Age <6 monthsUS acutely No Yes YesUS within 6 wk Yes No NoVCUG Only if US is abnormal, atypical UTI, or history of prior UTI

Age >6 months but <3 yearsUS acutely No Yes NoUS within 6 wk No No YesVCUG Only if US is abnormal, poor urine flow, non–Escherichia coli

infection, or family history of refluxAge >3 years

Study Responds well to Rx by 48 h Not atypical or recurrent UTI Atypical UTI History ofprior UTI

US acutely No Yes NoUS within 6 wk No No YesVCUG Only if US is abnormal

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— Pathogens other than E. Coli. P fimbri-ated E. coli bind to uroepithelial cells and resist to the normal urine flow. Non fimbri-ated bacteria ascend the urinary tract with the help of obstruction or reflux.

In a child with an abnormal US or the presence of one of the previous risk fac-tors, the Italian Guidelines 50 suggest further imaging of the urinary tract (cystography) and the renal parenchyma. In all children with an abnormal US or in whom VUR has been shown, a renal cortical scintigraphy (with DMSA) is recommended 6 months after the febrile UTI, in order to obtain a morphologic (presence of UTI related renal scarring) and functional evaluation (relative renal function) of the renal parenchyma. In children with febrile UTI presenting none of the risk factors discussed above no fur-ther imaging of the urinary tract and of the renal parenchyma is recommended. In case of recurrence of febrile UTIs, cystography and renal DMSA scan should be performed.

Conclusions

The management of febrile UTIs in chil-dren is changing and daily challenging cli-nicians. A definitive approach cannot be suggested yet, overall regarding the best management of children after a first UTI. On one hand, the concept of “primary renal damage” is growing as improved prenatal ultrasonography has revealed that major kidney damage in children is frequently re-lated to the presence of hypodysplasia, as-sociated with urologic abnormalities; on the other hand, infection-related renal scarring develops in some children, causing further damage in dysplastic kidneys, with the po-tential for late effects in previously normal kidneys.

In our opinion, the new Italian Guide-lines 50 and NICE guidelines 28 represents currently the best approach in the manage-ment of UTIs in children, with the only ad-junction for NICE guidelines to consider a renal scintigraphy 6 to 12 months after a UTI in order to predict severe VUR in very young children showing renal scarring, de-

at risk of loss of kidney function and who would require further assessment.

NICE guidelines 29 suggest to perform a DMSA scan 4-6 months after the acute in-fection to detect renal parenchymal defects only in children younger than 3 years with atypical and/or recurrent UTI.

When should further renal imaging (after RBUS) be performed? The new Italian Guidelines

According to the new Italian Guide-lines,50 if RBUS is normal and no risk fac-tors are present, further imaging is not indi-cated. If RBUS shows abnormalities or risk factors are present a complete morphologic evaluation of the kidney and urinary tract is indicated.

Suggested risk factors include: — In utero or postnatal US abnormali-

ties: hydronephrosis, ureteral dilatation, duplicated system, renal hypoplasia, loss of cortico-medullary differentiation or ab-normal parenchymal echogenicity, bladder wall thickening or irregularity, post-mictur-ating abnormal residual urine volume, blad-der diverticula.

— Family history of VUR: from a recent meta-analysis the prevalence of VUR is 27.4% (range 2.9-51.9) in siblings and 35.7% (range 16.4-61) in offspring screened.

— Septicemia: UTI is associated with sepsis in about 10% of infants. When sepsis is present the risk of urologic abnormalities is higher.

— Renal failure. — Male infants less than 6 months of

age. — Suspicion of noncompliance of the

family, which requires a more stringent di-agnostic approach, in order to avoid drop-outs and the loss to follow-up of children which could be at risk of renal damage.

— Micturition abnormalities or thickened bladder wall which may indicate posterior urethral valves.

— Absence of a clinical response to an-tibiotics within 72 hours, with persistence of fever.

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9. Normand IC, Smellie JM. Prolonged maintenance chemotherapy in the management of urinary infec-tion in childhood. Br Med J 1965;1:1023-6.

10. Politano VA, Leadbetter WF. An operative technique for the correction of vesicoureteral reflux. J Urol 1958;79:932-41.

11. Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux: two years’ observation in 96 children. Br Med J (Clin Res Ed) 1983;287:171-4.

12. Medical versus surgical treatment of primary vesi-coureteral reflux: report of the International Reflux Study Committee. Pediatrics 1981;67:392-400.

13. National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treat-ment and longterm management [Internet]. Available at http://www.nice.org.uk/nicemedia/pdf/CG54full-guideline.pdf [cited 2012, Feb 23].

14. Royal Children’s Hospital Melbourne. Clinical prac-tice guidelines [Internet]. Available at http://www.rch.org.au/clinicalguide/cpg.cfm?doc_id=5241) [cited 2012, Feb 23].

15. Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP, Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010;25:1463-9.

16. Marks SD, Gordon I, Tullus K. Imaging in childhood urinary tract infections: time to reduce investigations. Pediatr Nephrol 2008;23:9-17.

17. Mori R, Lakhanpaul M, Verrier-Jones K. Diagnosis and management of urinary tract infection in children: summary of NICE guidance. BMJ 2007;335:395-7.

18. Moorthy I, Easty M, McHugh K, Ridout D, Biassoni L, Gordon I. The presence of vesicoureteric reflux does not identify a population at risk for renal scarring fol-lowing a first urinary tract infection. Arch Dis Child 2005;90:733-6.

19. Venhola M, Hannula A, Huttunen NP, Renko M, Pok-ka T, Uhari M. Occurrence of vesicoureteral reflux in children. Acta Paediatr 2010;99:1875-8.

20. Keren R. Imaging and treatment strategies for chil-dren after first urinary tract infection. Curr Opin Pedi-atr 2007;19:705-10.

21. Merguerian PA, Sverrisson EF, Herz DB, McQuiston LT. Urinary tract infections in children: recommen-dations for antibiotic prophylaxis and evaluation: an evidencebased approach. Curr Urol Rep 2010;11:98-108.

22. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003;348:195-202.

23. Conway PH, Cnaan A, Zaoutis T, Henry BV, Grund-meier RW, Keren R. Recurrent urinary tract infections in children: risk factors and association with prophy-lactic antimicrobials. JAMA 2007;298:179-86.

24. Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophy-laxis after acute pyelonephritis: amulticenter, rand-omized, controlled study. Pediatrics 2006;117:626- 32.

25. Montini G, Rigon L, Zucchetta P, Fregonese F, Tof-folo A, Gobber D et al. IRIS Group. Prophylaxis after first febrile urinary tract infection in children? a mul-ticenter, randomized, controlled, noninferiority trial. Pediatrics 2008;122:1064-71.

26. Pennesi M, Travan L, Peratoner L, Bordugo A, Cat-taneo A, Ronfani L et al. North East Italy Prophylaxis in VUR Study Group. Is antibiotic prophylaxis in chil-dren with vesicoureteral reflux effective in preventing

tecting those children who are at risk of loss of kidney function and who would require further assessment. The value of antibiotic prophylaxis has been questioned, but on-going studies may help to answer these questions.

Riassunto

Infezioni del tratto urinario nei bambini: una re-view

La pielonefrite rappresenta la più frequente infe-zione grave in età pediatrica, tuttavia non è ancora chiaro quale sia la sua migliore gestione, soprat-tutto riguardo al follow-up in seguito a un primo episodio febbrile di infezione delle vie urinarie. In questo articolo verranno riassunte le attuali racco-mandazioni per la diagnosi, il trattamento, l’imaging e l’uso della profilassi antibiotica per i bambini con un primo episodio febbrile di infezione delle vie urinarie. Tuttavia, lo sviluppo di un unico proto-collo diagnostico universalmente accettato sembra ancora lontano.

Parole chiave: Tratto urinario, infezioni - Bambino - Ultrasonografia.

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