A contemporary overview of urinary tract infection (UTI) in children

Ranjit R Roy; Rummana T Tonny; Nadira Sultana; Abdullah Al Mamun; Tahmina Jesmin

doi:10.4103/pnjb.pnjb_10_22

REVIEW ARTICLE

Year : 2022 | Volume : 7 | Issue : 1 | Page : 19-28

A contemporary overview of urinary tract infection (UTI) in children

Ranjit R Roy, Rummana T Tonny, Nadira Sultana, Abdullah Al Mamun, Tahmina Jesmin
Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh

Date of Submission	08-Mar-2022
Date of Acceptance	13-Mar-2022
Date of Web Publication	31-May-2022

Correspondence Address:
Prof. Ranjit R Roy
Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pnjb.pnjb_10_22

Abstract

Urinary tract infection (UTI) is the most common and serious bacterial infection in the pediatric age group. It is more prevalent in girls than in boys, except in early infancy. Escherichia coli is responsible for 80–90% of cases of pediatric UTI. The occurrence and severity of this illness are largely mediated by bacterial virulence factors and host defense mechanism. The clinical manifestations of UTI in children are highly heterogeneous, and non-specific collection of urine sample to diagnose the condition accurately is quiet challenging for young pre-continent children. Till date, urine culture is the gold standard for diagnosing UTI. Selection of appropriate antibiotic for the treatment of UTI must be guided by the local guideline and current sensitivity pattern. Ideal imaging protocol and use of antibiotic prophylaxis are still a matter of debate. Current trend is less use of antibiotic prophylaxis due to increasing antibiotic resistance. Prophylaxis cannot alter the long-term consequences, like renal scarring in selected patients. The debate on the indication and duration of antibiotic prophylaxis is still ongoing. So, this review aimed to provide a contemporary overview on the pathogenesis, clinical findings, diagnosis, imaging investigation, treatment, complications, and preventive measures of UTI including chemoprophylaxis in pediatric population. It also highlights the conflicting recommendations of international guidelines, which reveal the necessity of further research to establish the tailored approach of pediatric UTI.

Keywords: Children, clinical and laboratory parameter, renal scar, UTI

How to cite this article:
Roy RR, Tonny RT, Sultana N, Mamun AA, Jesmin T. A contemporary overview of urinary tract infection (UTI) in children. Paediatr Nephrol J Bangladesh 2022;7:19-28

How to cite this URL:
Roy RR, Tonny RT, Sultana N, Mamun AA, Jesmin T. A contemporary overview of urinary tract infection (UTI) in children. Paediatr Nephrol J Bangladesh [serial online] 2022 [cited 2023 Oct 4];7:19-28. Available from: http://www.pnjb-online.org/text.asp?2022/7/1/19/346341

Introduction

Urinary tract infection (UTI) is one of the most common bacterial infections in children which accounts for 5–14% of pediatric emergency visits.^[1],[2] It can occur in children with normal urinary tracts^[3] or can be the first sign of children with congenital anomaly of kidney and urinary tract (CAKUT) in 30% of the cases. So, a single episode of UTI in children may be the sentinel event for an underlying renal abnormality.^[4],[5],[6] When UTI involves the kidney, the condition is termed as pyelonephritis (PN).^[7] If children develop PN recurrently, it may damage the growing kidney by formation of scar that may predispose to hypertension (HTN), chronic kidney disease (CKD), and finally end-stage renal disease. That is why UTI is important for children.^[4],[8-10]

Prompt diagnosis and treatment are essential for the prevention of acute complications as well as renal scarring.^[11] However, establishing a suitable approach and identifying children who are at risk of renal damage is not a simple task.^[4] The tendency of UTI recurrence, associated morbidity, and problems with collection of a urine sample accurately offer a significant challenge to the clinician, parents, and children as well.^{[1],[12],[13]} Extensive research has been done on pediatric UTI regarding renal imaging indication and long-term antibiotic prophylaxis in the last two decades.^[11] Till date, the management of UTI in children remains controversial. Diagnosis, treatment, and follow-up of children with UTI are crucial issues for the pediatricians.^[4],[14] The purpose of this review is to summarize the current literature and guidelines on pediatric UTI as well as to give a contemporary overview regarding the assessment and management of UTI in children.

Epidemiology and Risk Factors

Prevalence of UTI in children varies according to age, sex, race, circumcision status of male child, etc.^[2] At least one episode of UTI has been experienced by 8% of children between the ages of 1 month and 11 years.^[15],[16] After the initial episode, 12–30% of infants and children experience UTI recurrence during the first 6–12 months of their age.^[17],[18] It is more common in pre-term than term neonate^[19] with a male preponderance.^[6],[20] It is more common in boys (3.7%) when compared with girls (2%) in the first year of life. Beyond infancy, the condition is reversed as it is more prevalent in girls. The incidence in girls is 3% and it is 1% in boys during prepubertal age.^{[21],[22],[23]} Under 3 months of age, uncircumcised boys had a 20% higher risk of UTI compared with circumcised boys (2.4%).^{[24],[25],[26]} In both the groups, the prevalence tends to lower as the age increases.^[2] Considering race, the prevalence is two- to four-fold higher in Hispanic and white children than that in the black children.^{[27],[28],[29]} Ten percent of white febrile infants and toddlers will have a UTI, whereas 2% of similar black children will have so in the absence of another source of infection.^[2]

Additional factors those predispose children to higher risk of developing UTI are high grade vesico-ureteric reflux (VUR), CAKUT, bowel bladder dysfunction (BBD), instrumentation of the urinary tract (particularly indwelling bladder catheterization), kidney stone, sextual activity, diabetes, genetic factors, etc.^{[22],[26],[30-33]} Antibiotic therapy may change periurethral flora that may also predispose to UTI.^[34]

Risk factors for renal scarring due to acute PN (APN) include high-grade VUR (mostly grades 4 and 5),^[35],[36] fever for more than 3 days before the initiation of antibiotics,^{[37],[38],[39]} recurrent UTIs,^[36],[40-42] and organism other than Escherichia coli.^{[43],[44],[45]} A genetic predisposition has been found to be associated with recurrent UTI and renal scarring. The genes are HSPA1B gene, ACE I/D gene, toll-like receptor 4 gene, TGFβ gene, etc.^{[46],[47],[48],[49],[50],[51],[52]}

Etiology

E. coli is responsible for 80^–90% of all cases of UTIs in children.^{[19],[29],[53],[54]} Other common uropathogens are Klebsiella, Proteus, Enterococcus, and Enterobacter species.^[55],[56]Proteus infection is more common in uncircumcised boys probably due to its presence under the foreskin. It also predisposed to the formation of phosphate stone by splitting urea to ammonia causing alkalinization of urine and subsequently develops UTI.^[8] Organisms such as Pseudomonas, Group B Streptococcus, and Staphylococcus aureus are the causative agents of UTI in children with CAKUT, genitourinary surgery, catheter, and recent antibiotic treatment.^[24],[57]

Hematogenous spread of infection to the urinary tract is common in newborns and children with compromised immune system.^[2] Group B Streptococcus, S. aureus, Pseudomonas aeruginosa, Salmonella, and Candida may cause PN through hematogenous route.^{[2],[57],[58]}

Classification System of UTI

^[3]

1. According to site

Upper UTI

UTI involves kidneys (PN) and ureters (ureteritis);

Lower UTI

UTI involves bladder (cystitis) and urethra (urethritis).

2. According to severity

Mild UTI

when symptoms are mild and children are able to take oral fluid and medications;

Severe UTI

when symptoms are more severe such as fever >39°C, persistent vomiting, and dehydration present.

3. According to episode

Recurrent UTI

two or more episodes of UTIs with APN/upper UTI or one episode of UTI with APN plus one or more episodes of UTI with cystitis/lower UTI or three or more episodes of UTI with cystitis^[59];

Relapse

UTI with the same strain of organism;

Reinfection

UTI with a different strain or species of organism;

Breakthrough UTI

UTI occurring in patients receiving antimicrobial prophylaxis.

4. According to symptoms

Febrile UTI

UTI associated with temperature ≥38°C (100.4 F);

Symptomatic UTI

UTI associated with fever and/or urinary symptoms;

Asymptomatic bacteriuria (ABU)

presence of significant bacteria in urine without any symptom of UTI.

5. According to complicating factors

Uncomplicated UTI

UTI occurs in a patient with normal upper and lower urinary tract, normal renal function, competent immune system, and patients can be managed on outpatient basis.

Complicated UTI

UTI in newborns, kidney and urinary tract anomaly, urosepsis, organism other than E. coli, atypical clinical course, absence of clinical response to antibiotic within 72 h, renal abscess, abdominal and/or bladder mass, raised serum creatinine.

Complicated cystitis

children with comorbid medical conditions, underlying bladder pathology, indwelling bladder catheter, and atypical clinical course.^[11]

Definitions of Frequently Used Terms in UTI

Urinary tract infection (UTI)^[60]

UTI is defined as the invasion and multiplication of microorganisms in significant number within the urinary tract producing symptoms.

Atypical UTI (NICE guidelines)^[59]

UTI with one of the followings:

Seriously ill child

Poor urine flow (oliguria not due to dehydration or urinary retention)

Abdominal or bladder mass

Raised serum creatinine level (estimated glomerular filtration rate <80 mL/min/1.73 m²)

Septicemia

Failure to respond to treatment within 48 h

Non-E. coli UTI

Typical UTI

UTI without any of these conditions.

Presumed UTI

A combination of clinical features and positive urinalysis (bacteria, leukocyte esterase, nitrite, and/or ≥5 WBC/HPF) (Guideline, AAP 2011).^[41]

Definite UTI

A combination of clinical features, positive urinalysis, and a positive urine culture (Guideline, AAP 2011).^[41]

Masked (occult)

Younger kids with non-specific, ill understood, poorly expressed symptoms may be culture-negative and treated with antibiotics for undiagnosed fever.^[60]

Bowel bladder dysfunction (BBD)

Spectrum of signs and symptoms include incontinence, constipation and/encopresis associated with functional and behavioral abnormalities of the bowel, lower urinary tract, and pelvic floor.^[11]

Reflux nephropathy

Renal cortical abnormalities are associated with VUR.

Renal scarring

Acquired renal damage is due to APN.

Renal dysplasia

This includes congenital renal cortical abnormalities.

Pathogenesis

Most UTI results from ascending infection from periurethral colonization of uropathogenic bacteria. They migrate through the urethra to reach the bladder and finally to the kidney in a retrograde fashion.^[29],[61-63] Invasion of the kidney by a pathogenic organism initiates an intense inflammatory response that may lead to renal scarring.^[29] The pathogenesis of APN and renal scarring formation is a complex process that is not fully understood.^[11]

Virulence factors of pathogen and host defense mechanism: The virulence of uropathogenic strain of E. coli is largely mediated by the presence of P fimbriae (also known as PN-associated pili), lipopolysaccharide (LPS), and hemolysin.^[4],[11] Adhesin pap G mediates binding of P. fimbriae to uroepithelium, thereby adhering pathogen to the mucosa.^[11] LPS is an endotoxin that contains lipid A in the outer membrane and oligosaccharide core that determines the O-antigen. Lipid A component is responsible for the toxic effects such as fever and acute phase response. Hemolysins produced by uropathogenic strain of E. coli are pore-forming proteins. They increase the cell membrane permeability, thus exerting cytotoxic effect.^[4]

LPS binds with toll-like receptor 4 present in the uroepithelium and part of renal tubule. Their activation causes release of proinflammatory cytokines, chemokines, and recruitment of neutrophils and macrophages and generation of reactive oxygen species (ROS).^[64],[65] The proinflammatory responses result in killing of pathogen as well as damaging to the surrounding renal parenchyma. This ultimately causes development of fibrosis and scarring of renal tissue.^{[66],[67],[68],[69]} This process is initiated by macrophages and completed by neutrophils.^[70]

Clinical Manifestation

Clinical presentation of UTI in children is highly heterogeneous, which varies with age. Sometimes, symptoms can be quite obscure that mislead the diagnosis.^[71] So, the pediatricians should have a high index of suspicion regarding this common problem of children.

Newborns and infants less than 3 months may have vague and non-specific symptoms, including temperature instability (hyperthermia and fever), lethargy, irritability, apnea, convulsion, diarrhea, vomiting, poor sucking, failure to thrive, prolonged jaundice, malodorous urine, oliguria, or polyuria.^{[13],[56],[71]} There is a high probability of bacteremia and sepsis in the age group, and mortality rate is around 10%.^[31],[62]

Approximately 5% of infants less than 12 months with UTI have bacteremia that can lead to urosepsis.^[7],[72] The risk of co-existing meningitis and UTI is 1%.^[73]

In between 3 months and 2 years of age, unexplained fever is the most common and often the only presenting symptom of UTI.^{[1],[4],[71],[74]} Fever without a localizing sign or obvious source, UTI is a probability.^[2] According to the American Academy of Pediatrics (AAP) Guideline, UTI should be considered up to first 2 years of life including the newborn period when patients will come with unexplained fever.^[75]

The signs and symptoms are more specific in older children as they are able to verbalize symptoms. A classic study of 200 children demonstrated that fever and abdominal pain were the most common symptoms in 2–5-year-old children. The typical signs and symptoms of UTI were present beyond 5 years of age including fever, dysuria, frequency, urgency, suprapubic on flank pain, incontinence, and renal angle tenderness.^[76] Less commonly nocturnal enuresis of recent onset, frank hematuria can also occur. Girls are more commonly present with typical symptoms of cystitis during the adolescent period. They may present with similar symptoms while suffering from sexually transmitted infections or vaginitis.^[27],[77]

Concurrent presence of a weak urinary stream or dribbling of urine suggest neurogenic bladder or posterior urethral valve in boys.^[57]

Therefore, a thorough history taking and careful physical examination might be able to prompt diagnosis of UTI in children and thus prevent damage to the kidneys.

Urine Evaluation

•Urine sample collection

For pre-continent children^[7]Non-invasive method: nappy pad, urine bag, clean catch.Invasive method: catheter, suprapubic aspiration (SPA)

Continent children can void on demand and can provide a mid-stream urine sample. The initial voided urine flushes away the skin flora from urethral orifice. Cleaning the external genitalia carefully with soap and water before taking urine sample further reduces contamination. This opportunistic collection technique is more acceptable for toilet trained children.^[78] Another reasonable alternative method of urine collection is the Quick–Wee method.^[79] In this method, suprapubic area is stimulated by using a cold water-soaked gauze and then mid-stream urine is collected in a sterile cup.^[80]

Contamination is a significant concern for girls and young uncircumcised boys. Girls may benefit from facing backward on the toilet, which splays the legs and labia, thereby reducing contamination from skin and vaginal surface. In case of uncircumcised boys, gentle retraction of prepuce may reduce contamination.^[11] UK general practitioners prefer non-invasive collection,^[81] whereas USA practitioners prefer catheterization and SPA.^[82] Urine sample should be collected before initiation of antibiotic therapy. Treatment should not be delayed in children with sepsis.^[7]

•Urinalysis

There are 3 screening methods of urinalysis^[3]:

Dipstick

Microscopy

Flow imaging analysis technology

The leukocyte esterase test on urine dipstick is a widely available screening test. Most uropathogens but not all (including Klebsiella and Enterococcus) convert nitrates into urinary nitrites.^[83] None of them is fully sensitive or specific for UTI. They are considered as a useful screening tool when used in combination. RBC and/or protein on urine dipstick is not specific for UTI,^[11] but dipsticks have a good negative predictive value to exclude the diagnosis of UTI.^[84]

Sensitivity and specificity of components of urinalysis are summarized in [Table 1]^[60]:

Table 1: Urinalysis and newer screening tests

Click here to view

•Urine culture

Urine culture is the gold standard technique for the diagnosis of UTI.^[85] The colony count threshold varies between methods of collection and recommendations of guidelines.^[86],[87] While samples are obtained by catheterization, the threshold is 50,000 CFU/mL. For clean catch urine and SPA, it is 100,000(10⁵) and 1000(10³) CFU/mL, respectively.^[11] According to AAP UTI guidelines 2011, urinalysis positivity and >50,000 CFU/mL of a single uropathogen found in the specimen obtained from bladder catheterization suggest true urine infection.^[41] Any growth on SPA constitutes a positive culture, suggested by many guidelines.^[86] In febrile children <4 months of age, a cut-off value of 10³ CFU/mL can be considered depending on clinical and laboratory findings as well as a correct sampling method.^[88]

Additional Laboratory Studies

^[60]

Blood culture: Recommended for febrile infants under 3 months of age or fever without a source in a toxic-appearing infant.

Lumber puncture: Recommended for all febrile neonates or ill-appearing infants of <3 months old.^[89]

Others: This includes complete blood count, C-reactive protein (CRP), procalcitonin, metabolic panel, electrolyte, renal function tests (blood urea and serum creatinine), ferritin, proinflammatory cytokines, etc.

Test of cure after treatment: These are not routinely recommended and should be done only if clinically indicated.^[90],[91]

Common Errors in the UTI Diagnosis

•Contamination

Bag urine specimen possesses 80% contamination rate.^[41],[92] If bag specimen is sent for culture, a higher threshold such as >100,000 CFU/mL should be considered.^[89]

Presence of two or more organisms on urine culture is consistent with contaminations,^[93] and non-uropathogens (Lactobacillus, Corynebacterium, Viridans streptococci, coagulase-negative Staphylococci) are considered as contaminants in children.^[41]

•Asymptomatic bacteriuria (ABU)

Colonization of pathogen within the bladder in the absence of active inflammation is termed as ABU. It is more common in girls. A recent meta-analysis has been reported a lower prevalence of <0.5%,^[94] although its incidence is estimated at 1–3%. It usually resolves spontaneously within few months to few years.^{[95],[96],[97]} Antibiotic therapy is not recommended for otherwise healthy individuals with ABU because it may promote antimicrobial resistance and increase the risk of symptomatic UTI.^{[98],[99],[100],[101]} ABU is more frequent in case of children with neurogenic bladder.^[102] It has been proposed that urinary biomarkers such as interleukin-6 and neutrophil gelatinase-associated lipocalin may be used to differentiate UTI from ABU. Further research is needed to establish the clinical utility of these emerging tests.^[84]

•Sterile pyuria

Sterile pyuria is defined as increased WBC count in urine in the absence of bacteria on urine culture.^[11] It may occur in partially treated UTI, appendicitis tuberculosis, fungal, viral, or parasite infections, acute glomerulonephritis, systemic lupus erythematosus, Kawasaki disease, foreign body (catheter), kidney stone, interstitial nephritis, analgesic nephropathy, and papillary necrosis.^[103],[104]

•Differentiation of APN from cystitis

Differentiation of APN from cystitis is difficult particularly for pre-verbal children. Sometimes, symptoms are so overlapping that it further makes it difficult to distinct the two conditions.^[11] The evidence suggests that children with very high leukocyte count, CRP, or procalcitonin level (>1 µg/mL) in serum are more likely to have APN,^{[69],[105-107]} although some authors suggest that the utility of these screening tests is limited.^[11]

Imaging

Renal imaging after UTI is needed to identify underlying renal or urinary tract abnormality and to assess the degree of renal injury. Recent guidelines suggest limited role of imaging investigations for children with UTI and these are summarized in [Table 2].

Table 2: Summary of imaging recommendations from selected international guidelines for young children with UTI

Click here to view

•Renal ultrasound (US)

Renal bladder ultrasound (US) should be performed in all infants (<2 years) with febrile UTI (AAP 2011) and in older children with recurrent UTIs to exclude any obstruction of the urinary tract. Abnormalities are found in 15% of the cases, and 1–2% of the cases can require drainage.^[111] During acute infection, it can mislead the diagnosis of urinary tract abnormalities. E. coli endotoxin may produce dilation, which might falsely reveal hydronephrosis, and edema can change the renal anatomy (size and shape of the kidney) and/or echogenicity of renal parenchyma. So, it can be deferred to 4–6 weeks until after resolution of acute infection depending on clinical situation of the patient. It should be recommended during acute illness if the patient is not responding to treatment (beyond 48–72 h) to diagnose complications such as renal abscess, occult obstruction, stone etc.^{[11],[41],[91]}

•VCUG

It is not routinely recommended after first febrile UTI as less than one-third of children with their first UTI have VUR and <10% of them have high-grade VUR (grades 4 and 5).^[35],[112] It should be considered after first UTI in children if abnormality is found in renal bladder US, UTI caused by atypical pathogen, complicated clinical course, known renal scarring.^{[41],[113-115]} For those who have positive family history of VUR or CAKUT after first febrile UTI, VCUG should be also considered for them.^[11]

•DMSA

This is not routinely recommended for all children with UTI.^[91] DMSA can detect PN by perfusion defect (reduced uptake) up to 6 weeks of acute phase of a febrile UTI and can also demonstrate renal scars after 3–6 months.^[3],[116] In the absence of baseline scan (pre-APN), it is difficult to distinguish acquired from congenital lesions. Cortical defects on DMSA scan may be due to preexisting lesions (congenital) or may be an acute inflammatory reaction associated with APN (acquired).^[117] Diffusion weighted magnetic resonance imaging has been shown to diagnose APN accurately and late renal scars as well. So, it can be an alternative to DMSA.^[118]

Complications of UTI

Acute complications include dehydration, electrolyte imbalance, febrile convulsion, renal abscess, complete occlusion of preexisting and partial pelviureteric junction obstruction, urosepsis, and acute kidney injury (AKI). AKI may occur due to dehydration, and nephrotoxic drugs are non-steroidal anti-inflammatory drugs, antibiotics, etc. Long-term complication of APN is renal scarring.^[11] The prevalence of renal scarring after febrile UTI is 15%^[119] and after the first UTI, it is 3% and after three or more febrile UTIs, it is 29%.^[43],[120] Renal scarring subsequently may cause HTN, proteinuria, and CKD.^[121]

Treatment

•Antibiotic therapy

The choice of empirical antibiotic therapy must be guided by local guidelines and current sensitivity patterns, as it can vary significantly between countries and hospitals.^[82] Neonates and young febrile infants (<2 months) are recommended for inpatient parenteral antibiotic therapy because of higher risk of urosepsis and possibility of underlying structural abnormality.^[122] AAP recommends that inpatient parenteral therapy should be considered for clinically toxic-appearing children, severely dehydrated children, and those unable to tolerate oral fluid or medications.^[41] Failed outpatient therapy, poor adherence to medication, renal or perinephric abscess, immunocompromised children should also consider impatient management.^[4] Shifting of intravenous to oral therapy is recommended when there is clinical improvement. Oral antibiotic is to be continued to complete a total course of 14 days.^[123] However, majority of pediatric UTIs can be treated effectively in an outpatient basis with oral antibiotic as per culture sensitivity and in vitro response pattern.^[60] For uncomplicated febrile UTIs, 7–10 days oral antibiotic therapy is adequate.^[11] AAP recommended that all UTI (both cystitis and PN) should be treated for 7–14 days.^[82] NICE guideline suggests 7–10 days therapy for PN and 3 days for children >3 months with cystitis.^[81] Follow-up should be considered after 48–72 h to assess response to therapy.^[91] It has been reported that fever resolves within first 24 h in 68% of children and by 72 h in 92% of the cases.^[124] If patient remains febrile beyond 72 h, the clinician should consider suppurative complications as well as resistant or unusual causative organism.^[91]In vivo and in vitro antibiotic sensitivity patterns may not be the same always. So, clinical response is more important.^[60]

•Role of surgery

In the case of obstructive uropathy, stent or nephrostomy may be required temporarily.^[6] Suppurative complications such as renal or perinephric abscess may need surgical or percutaneous drainage.^[125] Although surgical treatment is not the first-line therapy for VUR, the chief surgical approach includes ureteric reimplantation (open or laparoscopic), endoscopic subureteral, or intraureteral injection of bulking agents (deflux-dextranomer hyaluronidase).^[11],[126]

Prevention of UTI

•Chemoprophylaxis

Antimicrobial prophylaxis is commonly used to prevent UTI recurrence in children.^[3] The effectiveness of antimicrobial prophylaxis in this regard has been extensively studied. A large multi-center study (RIVUR trial) found that antimicrobial prophylaxis reduced the risk of UTI recurrence by 50% in children with grades I–IV VUR, but the incidence of renal scarring did not differ significantly between the prophylaxis and placebo group (11.9% and 10.2%, respectively).^[127] Rather, antibiotic resistance is a major risk of long-term prophylaxis.^[128] Another placebo-controlled double-blind (PRIVENT study) trial has reported similar results.^[11] Combined results of RIVUR and the Careful Urinary Tract Infection Evaluation (CUTIE) studies found the beneficial effects of prophylaxis in toilet-trained children with VUR and BBD.^[129] No study has revealed any beneficial effect of prophylaxis for the prevention of renal scarring.^[11] So, limited and selected use of prophylaxis is the current trend. While used, it is to be reviewed every 6 months for assessing the benefits and deciding the continuation or stoppage or any change of prophylaxis needed.^[59]

Vitamin A prevents renal scarring in APN and vitamin E ameliorates symptoms of UTI. Treatment of physiological phimosis with local steroid application also reduces incidence of UTI. Intravesical gentamycin instilled in a patient on maintenance CIC also prevents UTI. Role of probiotics in UTI prevention is going to be established.

•Dietary supplements

Cranberry products, mostly available as liquid preparation (juice or syrup), also in tablets or capsule form, have shown some benefits for reducing the risk of UTI in children, although results are conflicting between different studies.^[59] The efficiency of probiotics in this context is also uncertain.^[130] Vitamin A prevents renal scarring and vitamin E ameliorates the symptoms of UTI.^[6]

•Care of prepuce

Daily retraction, cl eaning, and use of topical steroid in the presence of phimosis in boys significantly reduce UTI recurrence.^[131] If unsuccessful, circumcision should be considered.^[6],[11]

•BBD (bowel bladder dysfunction)

Febrile and/or recurrent UTI mandate the exclusion of BBD in case of toilet-trained children.^[6] Complete bladder emptying using double voiding, prevention or treatment of constipation, and good perineal hygiene are also important to lower the rate of UTI recurrence.^[8]

Conclusion

Accurate diagnosis of pediatric UTI needs a good clinical assessment along with a reliable laboratory result on an uncontaminated specimen of urine. Clinical diagnosis is sometimes misleading and collection procedure is not a simple task for pre-continent children. Prompt diagnosis and initiation of early therapy are mandatory to prevent short-term morbidity such as urosepsis and long-term complications such as renal scarring as well. International guidelines have conflicting recommendations regarding sample collection methods, imaging indications, duration of antibiotic therapy, and efficacy of antibiotic prophylaxis. Despite high prevalence of UTI in the pediatric age group, it has still many unresolved issues. Target research is needed in future to find out the knowledge gap and cost-effective care for UTI in children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Leung AKC, Wong AHC, Leung AAM, Hon KL Urinary tract infection in children. Recent Pat Inflamm Allergy Drug Discov 2019;13:2-18.
2.	Balighian E, Burke M Urinary tract infections in children. Pediatr Rev 2018;39:3-12.
3.	A‘t Hoen L, Bogaert G, Radmayr C, Dogan HS, Nijman RJ, Quaedackers J, et al. Update of the EAU/ESPU Guidelines on urinary tract infections in children. J Pediatr Urol 2021;17:200-7.
4.	E Silva ACS, Oliveira EA, Mak RH Urinary tract infection in pediatrics: An overview. J Pediatr (Rio J) 2020;96(Suppl. 1):65-79.
5.	Arshad M, Seed PC Urinary tract infections in the infant. Clin Perinatol 2015;42:17-28, vii.
6.	Sastre JB, Aparicio AR, Cotallo GD, Colomer BF, Hernández MC; Grupo de Hospitales Castrillo. Urinary tract infection in the newborn: Clinical and radio imaging studies. Pediatr Nephrol 2007;22: 1735-41.
7.	Kaufman J, Temple-Smith M, Sanci L Urinary tract infections in children: An overview of diagnosis and management. BMJ Paediatr Open 2019;3:e000487.
8.	Rees L, Bochenhaver D, Webb NJH, Punaro MG Urinary tract infection. In: Rees L, Bochenhaver D, Webb NJH, Punaro MG, editors. Paediatric Nephrology (Oxford Specialist Handbooks in Paediatrics). 3rd ed. UK: Oxford University; 2019. p. 87-102.
9.	Paintsil E Update on recent guidelines for the management of urinary tract infections in children: The shifting paradigm. Curr Opin Pediatr 2013;25:88-94.
10.	Coulthard MG, Lambert HJ, Vernon SJ, Hunter EW, Keir MJ, Matthews JN Does prompt treatment of urinary tract infection in preschool children prevent renal scarring: Mixed retrospective and prospective audits. Arch Dis Child 2014;99:342-7.
11.	Mattoo TK, Shaikh N, Nelson CP Contemporary management of urinary tract infection in children. Pediatrics 2021;147:1-12.
12.	Leung AC, Robson WM Urinary tract infection in infancy and childhood. Adv Pediatr 1991;38:257-85.
13.	Leung AK Common Problems in Ambulatory Pediatrics: Specific Clinical Problems. Vol. 1. New York: Nova Science Publishers, Inc.; 2011. p. 173-81.
14.	Williams GJ, Hodson EH, Isaacs D, Craig JC Diagnosis and management of urinary tract infection in children. J Paediatr Child Health 2012;48:296-301.
15.	Hoberman A, Chao HP, Keller DM, Hickey R, Davis HW, Ellis D Prevalence of urinary tract infection in febrile infants. J Pediatr 1993;123:17-23.
16.	Mårild S, Jodal U Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Paediatr 1998;87:549-52.
17.	Mangiarotti P, Pizzini C, Fanos V Antibiotic prophylaxis in children with relapsing urinary tract infections. J Chemother 2000;12:115-23.
18.	Nuutinen M, Uhari M Recurrence and follow-up after urinary tract infection under the age of 1 year. Pediatr Nephrol 2001;16:69-72.
19.	Schlager TA Urinary tract infections in infants and children. Microbiol Spect 2016;4:4-5.
20.	Hari P, Srivastava RN Urinary tract infections. In: Srivastava RN, Bagga A, editors. Paediatric Nephrology. 6th ed. New Delhi: Jaypee Brothers; 2016. p. 265-89.
21.	Zorc JJ, Levine DA, Platt SL, Dayan PS, Macias CG, Krief W, et al; Multicenter RSV-SBI Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Clinical and demographic factors associated with urinary tract infection in young febrile infants. Pediatrics 2005;116:644-8.
22.	Shaikh N, Morone NE, Bost JE, Farrell MH Prevalence of urinary tract infection in childhood: A meta-analysis. Pediatr Infect Dis J 2008;27:302-8.
23.	Kanellopoulos TA, Salakos C, Spiliopoulou I, Ellina A, Nikolakopoulou NM, Papanastasiou DA First urinary tract infection in neonates, infants and young children: A comparative study. Pediatr Nephrol 2006;21:1131-7.
24.	Hodson EM, Craig JC Urinary tract infections in children. In: Avneu EV, Harmon WE, Niaudet p, et al., editors. Pediatric Nephrology. 7th ed. Berlin, Germany: Springer; 2016. p. 1695-714.
25.	Panaretto K, Craig J, Knight J, Howman-Giles R, Sureshkumar P, Roy L Risk factors for recurrent urinary tract infection in preschool children. J Paediatr Child Health 1999;35:454-9.
26.	Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R Recurrent urinary tract infections in children: Risk factors and association with prophylactic antimicrobials. J Am Med Assoc 2007;298:179-86.
27.	Schmidt B, Copp HL Work-up of pediatric urinary tract infection. Urol Clin North Am 2015;42:519-26.
28.	Jackson EC Urinary tract infections in children: Knowledge updates and a salute to the future. Pediatr Rev 2015;36:153-64; quiz 165-6.
29.	Shaikh N, Hoberman A, Mattoo TK Urinary tract infections in children: Epidemiology and risk factors. UpToDate. Waltham, MA (Accessed on August 10, 2018). 2019.
30.	Hellerstein S Urinary tract infections in children: Why they occur and how to prevent them. Am Fam Physician 1998;57:2440-6, 2452-4.
31.	Ginsburg CM, McCracken GH Jr. Urinary tract infections in young infants. Pediatrics 1982;69:409-12.
32.	Wiswell TE, Miller GM, Gelston HM Jr, Jones SK, Clemmings AF Effect of circumcision status on periurethral bacterial flora during the first year of life. J Pediatr 1988;113:442-6.
33.	Godaly G, Ambite I, Svanborg C Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis 2015;28:88-96.
34.	Lidefelt KJ, Bollgren I, Nord CE Changes in periurethral microflora after antimicrobial drugs. Arch Dis Child 1991;66:683-5.
35.	Shaikh N, Ewing AL, Bhatnagar S, Hoberman A Risk of renal scarring in children with a first urinary tract infection: A systematic review. Pediatrics 2010;126:1084-91.
36.	Mattoo TK, Chesney RW, Greenfield SP, Hoberman A, Keren R, Mathews R, et al; RIVUR Trial Investigators. Renal scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. Clin J Am Soc Nephrol 2016;11:54-61.
37.	Karavanaki KA, Soldatou A, Koufadaki AM, Tsentidis C, Haliotis FA, Stefanidis CJ Delayed treatment of the first febrile urinary tract infection in early childhood increased the risk of renal scarring. Acta Paediatr 2017;106:149-54.
38.	Oh MM, Kim JW, Park MG, Kim JJ, Yoo KH, Moon D The impact of therapeutic delay time on acute scintigraphic lesion and ultimate scar formation in children with first febrile UTI. Eur J Pediatr 2012;171:565-70.
39.	Shaikh N, Mattoo TK, Keren R, Ivanova A, Cui G, Moxey-Mims M, et al. Early antibiotic treatment for pediatric febrile urinary tract infection and renal scarring. JAMA Pediatr 2016;170:848-54.
40.	Jodal U The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1987;1:713-29.
41.	Roberts KB, American Academy of Pediatrics. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: Clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595-610.
42.	Shaikh N, Haralam MA, Kurs-Lasky M, Hoberman A Association of renal scarring with number of febrile urinary tract infections in children. JAMA Pediatr 2019;173:949-52.
43.	Shaikh N, Craig JC, Rovers MM, Da Dalt L, Gardikis S, Hoberman A, et al. Identification of children and adolescents at risk for renal scarring after a first urinary tract infection: A meta-analysis with individual patient data. JAMA Pediatr 2014;168:893-900.
44.	Rushton HG, Majd M, Jantausch B, Wiedermann BL, Belman AB Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99mTechnetium-dimercaptosuccinic acid scintigraphy. J Urol 1992;147:1327-32.
45.	Jakobsson B, Berg U, Svensson L Renal scarring after acute pyelonephritis. Arch Dis Child 1994;70:111-5.
46.	Karoly E, Fekete A, Banki NF, Szebeni B, Vannay A, Szabo AJ, et al. Heat shock protein 72 (HSPA1B) gene polymorphism and toll-like receptor (TLR) 4 mutation are associated with increased risk of urinary tract infection in children. Pediatr Res 2007;61:371-4.
47.	Akil I, Ozkinay F, Onay H, Canda E, Gumuser G, Kavukcu S Assessment of toll-like receptor-4 gene polymorphism on pyelonephritis and renal scar. Int J Immunogenet 2012;39:303-7.
48.	Zaffanello M, Tardivo S, Cataldi L, Fanos V, Biban P, Malerba G Genetic susceptibility to renal scar formation after urinary tract infection: A systematic review and meta-analysis of candidate gene polymorphisms. Pediatr Nephrol 2011;26:1017-29.
49.	Harshman VP, Kryuchko TO, Kolenko IO, Kushnereva TV, Tkachenko OY Role of genetic mutations in development of immunological and clinical disorders in children with chronic pyelonephritis. Wiad Lek 2017;70:47-51.
50.	Hussein A, Askar E, Elsaeid M, Schaefer F Functional polymorphisms in transforming growth factor-beta-1 (TGFβ-1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection. Nephrol Dial Transpl 2010;25:779-85.
51.	Savvidou A, Bitsori M, Choumerianou DM, Karatzi M, Kalmanti M, Galanakis E Polymorphisms of the TNF-alpha and ACE genes, and renal scarring in infants with urinary tract infection. J Urol 2010;183:684-7.
52.	Zaffanello M, Malerba G, Cataldi L, Antoniazzi F, Franchini M, Monti E, et al. Genetic risk for recurrent urinary tract infections in humans: A systematic review. J Biomed Biotechnol 2010; 2010:321082.
53.	Korbel L, Howell M, Spencer JD The clinical diagnosis and management of urinary tract infections in children and adolescents. Paediatr Int Child Health 2017;37:273-9.
54.	Morello W, La Scola C, Alberici I, Montini G Acute pyelonephritis in children. Pediatr Nephrol 2016;31:1253-65.
55.	Edlin RS, Shapiro DJ, Hersh AL, Copp HL Antibiotic resistance patterns of outpatient pediatric urinary tract infections. J Urol 2013;190:222-7.
56.	Zorc JJ, Kiddoo DA, Shaw KN Diagnosis and management of pediatric urinary tract infections. Clin Microbiol Rev 2005;18: 417-22.
57.	Bell LE, Mattoo TK Update on childhood urinary tract infection and vesicoureteral reflux. Semin Nephrol 2009;29:349-59.
58.	Leung AK, Kao CP, Robson WL Urinary tract infection due to Salmonella Stanleyville in an otherwise healthy child. J Natl Med Assoc 2005;97:281-3.
59.	National Institute for Health and Care Excellence. Urinary tract infection in under 16s: Diagnosis and management [Internet]. London: NICE; 2007 [updated October 2018; cited February 2022]. Clinical Guideline [CG54]. Available from: https://www.nice.org.uk/guidance/cg54.
60.	Roy RR, Mamun AA, Jesmin T Urinary tract infection (UTI). In: Roy RR, Mamun AA, Jesmin T, Fatema K, editors. Pediatric Students Manual. 1st ed. Dhaka: Pediatric Study Group; 2020. p. 899-908.
61.	Clark CJ, Kennedy WA II, Shortliffe LD Urinary tract infection in children: When to worry. Urol Clin North Am 2010;37:229-41.
62.	Chang SL, Shortliffe LD Pediatric urinary tract infections. Pediatr Clin North Am 2006;53:379-400, vi.
63.	Schlager TA Urinary tract infections in infants and children. Infect Dis Clin North Am 2003;17:353-65, ix.
64.	Bergsten G, Wullt B, Svanborg C Escherichia coli, fimbriae, bacterial persistence and host response induction in the human urinary tract. Int J Med Microbiol 2005;295:487-502.
65.	Vaure C, Liu Y A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol 2014;5:316.
66.	Weisheit CK, Engel DR, Kurts C Dendritic cells and macrophages: Sentinels in the kidney. Clin J Am Soc Nephrol 2015;10:1841-51.
67.	Murugapoopathy V, McCusker C, Gupta IR The pathogenesis and management of renal scarring in children with vesicoureteric reflux and pyelonephritis. Pediatr Nephrol 2020;35:349-57.
68.	Roberts JA Etiology and pathophysiology of pyelonephritis. Am J Kidney Dis 1991;17:1-9.
69.	Lane MC, Mobley HL Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney. Kidney Int 2007;72:19-25.
70.	Glauser MP, Meylan P, Bille J The inflammatory response and tissue damage. Pediatric Nephrol 1987;1:615-22.
71.	Bauer R, Kogan BA New developments in the diagnosis and management of pediatric UTIs. Urol Clin North Am 2008;35:47-58; vi.
72.	Roman HK, Chang PW, Schroeder AR Diagnosis and management of bacteremic urinary tract infection in infants. Hosp Pediatr 2015;5:1-8.
73.	Tebruegge M, Pantazidou A, Clifford V, Gonis G, Ritz N, Connell T, et al. The age-related risk of co-existing meningitis in children with urinary tract infection. PLoS One 2011;6:e26576.
74.	Hudson A, Romao RLP, MacLellan D Urinary tract infection in children. CMAJ 2017;189:E608.
75.	American Academy of Pediatrics. Committee on Quality Improvement. Practice parameter: The diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103:843-52.
76.	Huppert JS, Biro F, Lan D, Mortensen JE, Reed J, Slap GB Urinary symptoms in adolescent females: STI or UTI? J Adolesc Health 2007;40:418-24.
77.	Copp HL, Shapiro DJ, Hersh AL National ambulatory antibiotic prescribing patterns for pediatric urinary tract infection, 1998-2007. Pediatrics 2011;127:1027-33.
78.	Vaillancourt S, McGillivray D, Zhang X, Kramer MS To clean or not to clean: Effect on contamination rates in midstream urine collections in toilet-trained children. Pediatrics 2007;119:e1288-93.
79.	Kaufman J, Tosif S, Fitzpatrick P, Hopper SM, Bryant PA, Donath SM, et al. Quick-Wee: A novel non-invasive urine collection method. Emerg Med J 2017;34:63-4.
80.	Kaufman J, Fitzpatrick P, Tosif S, Hopper SM, Donath SM, Bryant PA, et al. Faster clean catch urine collection (Quick-Wee method) from infants: Randomised controlled trial. Br Med J 2017;357:j1341.
81.	National Institute for Health and Clinical Excellence. Urinary tract infection in under 16s: Diagnosis and management.2017. Available from: https://www.nice.org.UK/guideline/CG54. [Last accessed on Feb 2022].
82.	Subcommittee on Urinary Tract Infection. Reaffirmation of AAP Clinical Practice Guideline: The diagnosis and management of the initial urinary tract infection in febrile infants and young children 2–24 months of age. Pediatrics 2016;138:e20163026.
83.	Cyriac J, Holden K, Tullus K How to use… urine dipsticks. Arch Dis Child Educ Pract Ed 2017;102:148-54.
84.	Fritzenwanker M, Imirzalioglu C, Chakraborty T, Wagenlehner FM Modern diagnostic methods for urinary tract infections. Expert Rev Anti Infect Ther 2016;14:1047-63.
85.	Stephens GM, Akers S, Nguyen H, Woxland H Evaluation and management of urinary tract infections in the school-aged child. Prim Care 2015;42:33-41.
86.	Okarska-Napierała M, Wasilewska A, Kuchar E Urinary tract infection in children: Diagnosis, treatment, imaging—Comparison of current guidelines. J Pediatr Urol 2017;13:567-73.
87.	Primack W, Bukowski T, Sutherland R, Gravens-Mueller L, Carpenter M What urinary colony count indicates a urinary tract infection in children? J Pediatr 2017;191:259-61.e1.
88.	Akagawa Y, Kimata T, Akagawa S, Fujishiro S, Kato S, Yamanouchi S, et al. Optimal bacterial colony counts for the diagnosis of upper urinary tract infections in infants. Clin Exp Nephrol 2020;24:253-8.
89.	UCSF Benioff Chlidren’s Hospitals (Internet). Oakland, CA: UCSF Benioff Children’s Hospital: 2016 (updated 2018; cited January 2022). Available from: https://www.ucsfbenioffchildrens.org.
90.	Currie ML, Mitz L, Raasch CS, Greenbaum LA Follow-up urine cultures and fever in children with urinary tract infection. Arch Pediatr Adolesc Med 2003;157:1237-40.
91.	Oreskovic NM, Sembrano EU Repeat urine cultures in children who are admitted with urinary tract infections. Pediatrics 2007;119:e325-9.
92.	Al-Orifi F, McGillivray D, Tange S, Kramer MS Urine culture from bag specimens in young children: Are the risks too high? J Pediatr 2000;137:221-6.
93.	Hay AD, Birnie K, Busby J, Delaney B, Downing H, Dudley J, et al. The diagnosis of urinary tract infection in young children (DUTY): A diagnostic prospective observational study to derive and validate a clinical algorithm for the diagnosis of urinary tract infection in children presenting to primary care with an acute illness. Health Technol Assess 2016;20:1-294.
94.	Shaikh N, Osio VA, Wessel CB, Jeong JH Prevalence of asymptomatic bacteriuria in children: A meta-analysis. J Pediatr 2020;217:110-7.e4.
95.	Linshaw M Asymptomatic bacteriuria and vesicoureteral reflux in children. Kidney Int 1996;50:312-29.
96.	Wettergren B, Jodal U Spontaneous clearance of asymptomatic bacteriuria in infants. Acta Paediatr Scand 1990;79:300-4.
97.	Gillenwater JY, Harrison RB, Kunin CM Natural history of bacteriuria in schoolgirls: A long-term case-control study. New Engl J Med 1979;301:396-9.
98.	Fitzgerald A, Mori R, Lakhanpaul M Interventions for covert bacteriuria in children. Cochrane Database Syst Rev 2012;301:CD006943.
99.	Hansson S, Jodal U, Norén L, Bjure J Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 1989;84:964-8.
100.	Nicolle LE, Gupta K, Bradley SF, Colgan R, DeMuri GP, Drekonja D, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis 2019;68:1611-5.
101.	Hansson S, Jodal U, Lincoln K, Svanborg-Edén C Untreated asymptomatic bacteriuria in girls: II—Effect of phenoxymethylpenicillin and erythromycin given for intercurrent infections. Br Med J 1989;298:856-9.
102.	Ottolini MC, Shaer CM, Rushton HG, Majd M, Gonzales EC, Patel KM Relationship of asymptomatic bacteriuria and renal scarring in children with neuropathic bladders who are practicing clean intermittent catheterization. J Pediatr 1995;127:368-72.
103.	Wise GJ, Schlegel PN Sterile pyuria. N Engl J Med 2015;372: 1048-54.
104.	Glen P, Prashar A, Hawary A Sterile pyuria: A practical management guide. Br J Gen Pract 2016;66:e225-7.
105.	Zhang H, Yang J, Lin L, Huo B, Dai H, He Y Diagnostic value of serum procalcitonin for acute pyelonephritis in infants and children with urinary tract infections: An updated meta-analysis. World J Urol 2016;34:431-41.
106.	Leroy S, Romanello C, Galetto-Lacour A, Smolkin V, Korczowski B, Rodrigo C, et al. Procalcitonin to reduce the number of unnecessary cystographies in children with a urinary tract infection: A European validation study. J Pediatr 2007;150:89-95.
107.	Zaffanello M, Brugnara M, Franchini M, Fanos V Is serum procalcitonin able to predict long-term kidney morbidity from urinary tract infections in children? Clin Chem Lab Med 2008;46:1358-63.
108.	Robinson JL, Finlay JC, Lang ME, Bortolussi R; Canadian Paediatric Society, Infectious Diseases and Immunization Committee, Community Paediatrics Committee. Urinary tract infections in infants and children: Diagnosis and management. Paediatr Child Health 2014;19:315-25.
109.	Stein R, Dogan HS, Hoebeke P, Kočvara R, Nijman RJ, Radmayr C, et al; European Association of Urology; European Society for Pediatric Urology. Urinary tract infections in children: EAU/ESPU guidelines. Eur Urol 2015;67:546–58.
110.	Pérez RP, Ortega MJ, Álvarez JA, Baquero-Artigao F, Rico JC, Zúñiga RV, et al. Recommendations on the diagnosis and treatment of urinary tract infection. Anales de Pediatría (Engl Ed) 2019;90: 400-e1.
111.	Whiting P, Westwood M, Watt I, Cooper J, Kleijnen J Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: A systematic review. BMC Pediatr 2005;5:4.
112.	Bahat H, Ben-Ari M, Ziv-Baran T, Neheman A, Youngster I, Goldman M Predictors of grade 3–5 vesicoureteral reflux in infants≤ 2 months of age with pyelonephritis. Pediatr Nephrol 2019;34: 907-15.
113.	Ammenti A, Alberici I, Brugnara M, Chimenz R, Guarino S, La Manna A, et al; Italian Society of Pediatric Nephrology. Updated Italian recommendations for the diagnosis, treatment and follow-up of the first febrile urinary tract infection in young children. Acta Paediatr 2020;109:236-47.
114.	Mori R, Lakhanpaul M, Verrier-Jones K Diagnosis and management of urinary tract infection in children: Summary of NICE guidance. Br Med J 2007;335:395-7.
115.	Pauchard JY, Chehade H, Kies CZ, Girardin E, Cachat F, Gehri M Avoidance of voiding cystourethrography in infants younger than 3 months with Escherichia coli urinary tract infection and normal renal ultrasound. Arch Dis Child 2017;102:804-8.
116.	Quirino IG, Silva JM, Diniz JS, Lima EM, Rocha AC, Simões e Silva AC, et al. Combined use of late phase dimercapto-succinic acid renal scintigraphy and ultrasound as first line screening after urinary tract infection in children. J Urol 2011;185: 258-63.
117.	Ditchfield MR, Summerville D, Grimwood K, Cook DJ, Powell HR, Sloane R, et al. Time course of transient cortical scintigraphic defects associated with acute pyelonephritis. Pediatr Radiol 2002;32:849-52.
118.	Bosakova A, Salounova D, Havelka J, Kraft O, Sirucek P, Kocvara R, et al. Diffusion-weighted magnetic resonance imaging is more sensitive than dimercaptosuccinic acid scintigraphy in detecting parenchymal lesions in children with acute pyelonephritis: A prospective study. J Pediatr Urol 2018;14:269.e1-7.
119.	Snodgrass WT, Shah A, Yang M, Kwon J, Villanueva C, Traylor J, et al. Prevalence and risk factors for renal scars in children with febrile UTI and/or VUR: A cross-sectional observational study of 565 consecutive patients. J Pediatr Urol 2013;9:856-63.
120.	Roberts KB Urinary tract infections and renal damage: Focusing on what matters. JAMA Pediatr 2014;168:884-5.
121.	Mattoo TK Vesicoureteral reflux and reflux nephropathy. Adv Chronic Kidney Dis 2011;18:348-54.
122.	Nandagopal R, Vaidyanathan P, Kaplowitz P Transient pseudohypoaldosteronism due to urinary tract infection in infancy: A report of 4 cases. Int J Pediatr Endocrinol 2009;2009:195728.
123.	Brady PW, Conway PH, Goudie A Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics 2010;126:196-203.
124.	Bachur R Nonresponders: Prolonged fever among infants with urinary tract infections. Pediatrics 2000;105:E59.
125.	Jeradi KE, Jackson EC Urinary tract infections. In: Kliegman RM, Geme St, Blum N et al, editors. Nelson Textbook of Pediatrics. 21st ed. Philadelphia: Elsevier; 2016. p. 2789-95.
126.	Meena J, Hari P Vesicoureteral reflux and recurrent urinary tract infections. Asian J Pediatr Nephrol 2019;2:61.
127.	RIVUR Trial Investigators. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014;370:2367-76.
128.	Selekman RE, Shapiro DJ, Boscardin J, Williams G, Craig JC, Brandström P, et al. Uropathogen resistance and antibiotic prophylaxis: A meta-analysis. Pediatrics 2018;142:e20180119.
129.	Shaikh N, Hoberman A, Keren R, Gotman N, Docimo SG, Mathews R, et al. Recurrent urinary tract infections in children with bladder and bowel dysfunction. Pediatrics 2016;137:e20152982.
130.	Durham SH, Stamm PL, Eiland LS Cranberry products for the prophylaxis of urinary tract infections in pediatric patients. Ann Pharmacother 2015;49:1349-56.
131.	Simoes e Silva AC, Oliveira EA Update on the approach of urinary tract infection in childhood. Jornal de Pediatría 2015;91:S2-10.