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Urinary tract infections in children: up-date

Colavita L.1, Chimenz R.2, Conti G.2, Fede C.2

1Unit of Genetics and Pediatric Immunology, University of  Messina, Italy

2Unit of Pediatric Nephrology and Rheumatology with Dialysis, University of  Messina, Italy

Introduction

The urinary tract is a common site of infection, especially in children younger than 2 years. In fact, Urinary Tract Infection (UTI) is a really common disease with a prevalence ranging from 2% to 8% throughout childhood. [1]

More studies show that in children with an age less than 2 years and with fever of unknown origin, the prevalence is 5%. In the first three months of life there is a higher incidence in males, with a ratio ranging from 2:1 to 5:1; in children from 2 months to 2 years of age, uncircumcised males and females are equally likely to present UTI. In children over the age of 2 years, the real risk of UTI has been reported in numerous studies to be 1.1-1.8% in males and 3.3-7.8% in females. The increased risk of the female sex is due to the greater proximity between anal and urethral orifice, which favors the colonization and the subsequent ascending infection by enterobacteria. In fact, Escherichia coli is the commonest cause of UTI in children (60– 92%). Other common organisms include Klebsiella, Proteus, Enterococcus, and Enterobacter spp. We can find uncommon organisms like Pseudomonas, Group B Streptococcus, and Staphylococcus aureus, in patients with predisposing factors like anatomical defects, kidney stones, following genitourinary surgery or bladder catheterization, and following repeated courses with antibiotic treatments. Streptococcus group B is more common in small chlidren, while Staphylococcus saprophyticus is more frequent in adolescents. Staphylococcus aureus occurred in renal abscesses. The vesicoureteral reflux (VUR) is an important predisposing factors for recurrence since it is due to rising urine along the urinary tract. Others predisposing factors for infection include bacterial virulence factors and host defense mechanisms. The recurrence or the mismanagement of UTIs may be associated with scarring. It is a long term sequela which may cause hypertension, proteinuria, pregnancy-related complications, or even progressive renal failure. It is therefore important the prompt recognition of the infection and the start of an appropriate management of the patient, so as to avoid complications. [1, 2, 3, 4, 5]

Clinical manifestations

UTIs may occur in three ways: asymptomatic bacteriuria; infection limited to the urethra and bladder (cystitis or lower UTI) without systemic symptoms; kidneys infection (pyelonephritis or upper UTI) with systemic symptoms.

More guidelines, such as those of  the National Institute of Clinical Excellence (NICE 2007), the American Academy of Pediatrics (AAP 2011) and the Italian Society of Pediatric Nephrology (ISPN 2011), agree that the symptoms of a febrile UTI are non-specific, particularly in small children. [5, 6]

Asymptomatic bacteriuria (ABU) is defined as the detection by urine culture of a significant growth of a single organism [often>100, 000 colony-forming units (CFU)/ml] in an asymptomatic child without pyuria. The commonest bacterium is E. coli, characterized by low virulence. It may colonize the urinary tract but cannot usually injure the kidney. Frequently it’s an incidental finding which can be found in subsequent urine cultures. [1]

Fever, especially in younger children, may be the only symptom. In AAP practice parameters, the presence of high fever (axillary temperature > 39 ° C)  with clinical diagnosis of UTI is an important indicator of pyelonephritis compared with no fever (≤38°C) in those with cystitis. The symptoms may vary with age. [7]

Anamnestic risk factors for UTI are: weak urinary stream, clinical history suggestive of previous UTI, relapsing fever of unknown origin, prenatal diagnosis of renal abnormalities, positive family history for VUR or kidney disease, constipation, poor growth, alterations of bladder emptying, neurological bladder, abdominal mass, spinal injuries, high blood pressure. [1, 4]

Individual risk factors for UTI have been identified and are different depending on the sex of the patient:

-          Female sex: caucasian race, age < 12 months, axillary temperature > 39 ° C, fever lasting ≥ 2 days and no other infectious outbreaks;

-          Male sex: not african ethnicity, axillary temperature > 39 ° C, fever lasting > 24 hours and no other infectious outbreaks.

The circumcision is a protective factor (the risk of UTI is 4 to 20 times higher in uncircumcised children).

The fever is the commonest clinical sign in children younger than 12 months. In the first 3 months of life, other commoner signs are vomiting, lethargy and irritability, sometimes associated with loss of appetite and poor growth; rare are abdominal pain, jaundice, hematuria and  turbid and smelly urine. Between 3 and 12 months of age, the fever is often the only sign. Abdominal pain, loss of appetite and vomiting may be present. Rare are lethargy, irritability, hematuria, poor growth, turbid and smelly urine. In children older than 12 months, pollakiuria and dysuria are the commonest clinical sign, sometimes with  alterations of bladder emptying and / or of continence and abdominal pain. [2]

Genetic factors

Genetic risk factors are related to Toll-like receptors (TLRs). They belong to the family of Pattern Recognition Receptor (PRRs), part of the innate immunity, and can be soluble in various body fluid or expressed on the cellular surface. They recognize signaling molecules shared by pathogens (Pathogen-Associated Molecular Patterns, PAMPs), activate the first defensive answer against pathogens and regulate the differentiation of the naive-T cell and the expression of proinflammatory cytokines and chemokines. So they influence the adaptive immunity too. More studies showed that the ability of some persons to respond adequately to the PAMPs may be impaired by single nucleotide polymorphisms (SNPs) in the TLRs’ genes, resulting in a marked susceptibility to infectious or inflammatory diseases. [16] This is also true with regard to UTIs. For example, Cheng et al. have demonstrated that some genetic variants in TLR-2 (rs3804100, T1350C) may protect the host from severe UTIs. [17] Others studies show that genetic alterations that reduce TLR4 function are associated with asymptomatic bacteriuria, while polymorphisms reducing IRF3 (interferon regulatory factor 3) or CXCR1 expression are associated with acute pyelonephritis and an increased risk for renal scarring. [18]

Laboratory diagnosis

All guidelines agree that in case of child with fever but no apparent source for its should always speculate an UTI, and collect a sample for urinalysis and culture.

We can do diagnosis of UTI when the urinalysis shows pyuria and/or bacteriuria and there is a positive culture. With microscopic examination of uncentrifuged urine, pyuria is defined by more than 10 Withe Blood cells (WBC) /mm3. Regarding to the urine culture, it is necessary the finding of a bacterial count > 100, 000 CFU/ ml. For values ​​between 10, 000 and 100, 000 CFU / ml, the infection is doubtful, especially if there are more germs (which suggests an incorrect collection with contamination of the sample). [2, 4, 5, 7]

About the possibility of sample’s contamination, it is controversial the method of urine collection, considering that the technique of obtaining the urine can affect sample quality. The AAP stresses  that the urine sample should be obtained by bladder puncture or bladder catheterization, and that cultures from bags applied to the perineum have an unacceptably high false-positive rate. So they can be considered valid only in case of negative result. [7]

However bladder puncture and catheterization are invasive maneuvers and they cannot be used routinely in the clinical practice. The bladder puncture is considered the gold standard. It has a success rate ranging from 23% to 90% for its operator-dependence; the percentage increases to 100% if performed under ultrasound guidance, with increased costs. In this case, any growth is diagnostic for UTI with a probability > 99%. The bladder catheterization has a specificity between 83% and 89% when compared to the bladder puncture. If we evaluate as positive a bacterial growth > 1000 CFU/mm3, the specificity rises to 95-99%. In children who are toilet trained, the urine collection by clean catch has sensitivity from 75% to 100% and specificity from 57% to 100%. [7] For ISPN guidelines, in febrile child with general conditions past due or impaired, the urine sample should be collected with midstream urine collection and, if this is not possible quickly, the sample will collected by bladder catheterization. If the general conditions are good, the midstream urine collection should be attempted even if  the child has not yet reached the sphincter control. If this is not possible, can use a perineal bag. [4] For NICE guidelines, a clean catch urine sample is the recommended method for urine collection and only if it isn’t obtainable, other non-invasive methods such as perineal bag can be used. Catheter samples or bladder puncture are the last choices, when non-invasive methods cannot be used. [2]

In clinical practice, both in hospital and in the territory, the collection of urine in small children without sphincter control takes place primarily using adhesive bag on the perineal area. Recently, this method is considered acceptable although second choice.

Considering that urine culture results are not available for at least 24 hours, we need rapid tests  that will allow us to put the suspicion of UTI and that to enable us to promptly initiate empirical therapy. Urinalysis can be done using any kind of sample, including one collected from perineal bag, but it must be fresh (1 hour after voiding with maintenance at room temperature or 4 hours after voiding with refrigeration), to make sure sensitivity and specificity.

The urinalysis can be performed using rapid dipstick for the evaluation of leukocyte esterase (sensitivity 83%,   specificity 78%) and nitrite (sensitivity 53%,   specificity 98%), or by microscopic examination for white blood cells (sensitivity 73%,   specificity 81%)  and bacteria (sensitivity 81%,   specificity 83%).

The positivity for leukocyte esterase (as a surrogate marker for pyuria) and/or nitrites (that is converted from dietary nitrates by Gram-negative enteric bacteria in the urine) indicates a high risk of UTI. In this case, a urine culture, that is the gold standard for the diagnosis, must be effected.

Regarding to microscopic examination realized on fresh and Gram-stained specimen of uncentrifuged urine, the presence of bacteria correlates with 105 CFUs per mL in culture.  The addition of the evaluation of pyuria increase sensitivity, specificity, and positive predictive value of the test. [7]

With regard to blood tests to do in suspected UTI, in reference guidelines and in the more recent literature is not taken into consideration performing blood tests such as PCR and white blood cell counts for the distinction between high or low UTIs, because the two tests are not related to the site of infection. Among the various tests, procalcitonin appears to be the most reliable exam for the definition of infection localization. [4]

Instrumental diagnosis

It has been considered for a long time that recurrent UTIs during childhood and UTI-related renal scarring may lead to long-term clinical consequences such as chronic kidney damage (CKD), hypertension and pre-eclampsia. Routine antenatal ultrasound has shown that a large part of the changes previously attributed to post-infectious scarring is mainly due to congenital renal malformations, often associated with major urologic abnormalities. [8]

The aim of instrumental exams is to individuate renal and urologic malformations, including vesicoureteral reflux (VUR) that is the commonest one, and post-infectious renal scarring.

The AAP guidelines recommend (with an evidence quality  C) that any febrile child with UTIs should curry out renal and bladder ultrasonography (RBUS) to individuate anatomic alterations, that often need further assessments. Besides, through the RBUS, it’s possible evaluate the renal parenchyma and monitor the renal growth. The diffusion of prenatal ultrasonography has implemented the antenatal diagnosis of obstructive uropathy. The timing of RBUS depends on the clinical conditions: when the clinical status is unusually severe or we don’t observed a substantial clinical improvement, the RBUS is recommended during the first 2 days of treatment to recognize severe complications, like renal or perirenal abscesses or pyonephrosis  associated with obstructive uropathy. If we observe a substantial clinical improvement, RBUS isn’t necessary during the acute phase. It can be rather deceptive because the E. Coli endotoxin can make dilation of the urinary tract during the acute infection, that could lead to erroneous diagnosis of hydronephrosis, pyonephrosis, or obstruction. [7]

The ISPN guidelines have given the following indications for RBUS execution:

-          delayed or unsatisfactory response to treatment of the first febrile UTI;

-          abdominal mass or abnormal voiding;

-          the first febrile UTI caused by organisms other than E. coli;

-          recurrent UTIs in children who have had a satisfactory response to treatment of the first febrile UTI;

-          every child with first febrile UTI that cannot do an adequate follow-up.

Voiding cystourethrography (VCUG) is not a routine exam and should not be done after the first febrile UTI but only when RBUS demostrates hydronephrosis, scarring or other findings indicative of high-grade VUR or obstructive uropathy, and in other atypical or complex clinical circumstances (like treatment failure after 48-72 hours, urinary abnormalities, each child that cannot be adequately further follow-up, abdominal mass and  recurrent UTIs). The radiation dose from VCUG depends on the equipment that is used (conventional versus pulsed digital fluoroscopy) and it is related directly to the total fluoroscopy time. [4, 7] Besides there is an additional radiation exposure for nuclear scanning with technetium labeled dimercaptosuccinic acid (DMSA).

For this, we are seeing a rapid spread of cystosonography with echo contrast. It is an imaging modality developed to avoid x-ray exposure for the detection of VUR and that use US contrast media that can be administered intravesically. Comparison between voiding urosonography (VUS) and VCUG has revealed the high concordance between these imaging modalities for the diagnosis of VUR. [9, 14, 15]

Nuclear scanning with technetium labeled dimercaptosuccinic acid (DMSA) has the greatest sensitivity for detection of acute pyelonephritis. However, this examination is not helpful in the acute phase and is not suitable as a routine examination in the first febrile episode of UTI. [7] However nuclear scan can be used in case of recurrent UTI to detect later scarring.

The various guidelines (ISPN 2011; AAP 2011; NICE 2007; Royal Children’s Hospital of Melbourne, RCH 2006), have different point of view about the imaging recommendations.  For ISPN, AAP and RCH, the RBUS is the first imaging diagnostic test to use. For NICE guidelines, the routine use of imaging in the localization of a UTI is not recommended. Only infants and children with atypical UTI (seriously ill, poor urine flow, abdominal or bladder mass, raised creatinine, septicemia, failure to respond to correct antibiotic treatment within 48 hours, or infection with non–Escherichia coli organisms) should have ultrasound of the urinary tract during the acute infection. For infants younger than 6 months with first-time UTI that responds to treatment, ultrasound should be carried out within 6 weeks; it isn’t necessary for children older than 6 months.

Regarding to VCUG, for ISPN and AAP guidelines the indications are those already mentioned above. For NICE, in children younger than 6 months VCUG con be done only in case of positive ultrasonography and/or atypical UTI, while in children older than 6 months only if there are specific risk factors (dilatation on RBUS, poor urine flow, non–E. coli infection, or family history of VUR). For RCH, the VCUG indications are age < 6 months and/or positive ultrasonography.

Relatively to late DMSA scan, AAP and RCH don’t recommend this exam. ISPN advises its only if  positive ultrasonography and/or VUR detected by VCUG. For NICE, DMSA scan should be done  4 - 6 months following the acute infection  only in case of atypical UTI to detect renal parenchymal defects. [2, 4, 7, 10]

Therapy

An antibiotic therapy should be started immediately after the collection of  urine sample for culture. It should be based on clinical suspicion, positive urine test under the microscope and positive urine stick. Waiting for urine culture results, an empiric antibiotic therapy must be started, possibly based on the knowledge of local resistance. After the arriving of cultural exams results, the clinician should adjust the choice according to sensitivity testing of the isolated uropathogen.

ISPN and AAP guidelines are very similar to each other regarding the therapeutic approach. In case of uncomplicated UTI (febrile child with good general condition and able to take fluids and medication by mouth), oral therapy should be practiced. It is indicated the use of an oral antibiotic with a low resistance profile, like cephalosporin, amoxicillin-clavulanic acid or trimethoprim-sulfamethoxazole.

If the oral antibiotic cannot be used and in case of complicated UTI (septic appearance, vomiting, hyperthermia, severe-mid dehydration and prediction of poor compliance), parenteral antibiotic therapy  (cefotaxime, ceftriaxone or an aminoglycoside) should be used for 2-4 days, followed by an oral antibiotic for a total duration of 10 days. The recommended dosage of drugs is the average expected. It’s important that agents that are excreted in the urine but do not achieve therapeutic concentrations in the bloodstream, such as nitrofurantoin, should not be used to treat febrile infants with UTIs, because parenchymal and serum antimicrobial concentrations may be insufficient to treat pyelonephritis or urosepsis.

With regard to antibiotic prophylaxis, ISPN guidelines highlight that it should not be routinely recommended in infants and young children after the first episode of UTI, but only in case of recurrent UTIs after treatment of the acute episode until the instrumental tests; in VUR grade equal to or higher than the third or also in case of VUR grade lower than the third if there are frequent UTIs (> 3 episodes in 6 months or > 4 episodes in one year). However ISPN and AAP emphasize that there is a significant number of infants who develop pyelonephritis in whom VUR cannot be demonstrated, and the effectiveness of antimicrobial prophylaxis for patients who have VUR is doubted by several studies that have suggested that prophylaxis does not confer the desired benefit of preventing recurrent febrile UTIs. [4, 7]

Besides, it’s known that antibiotic prophylaxis influences the uropathogenic bacteria’s spectrum of resistance. For example, Cheng et al. underline that children receiving cephalosporin prophylaxis are more likely to have extended-spectrum beta-lactamase-producing bacteria or multidrug-resistant uropathogens other than E. coli for breakthrough urinary tract infections; therefore, these antibiotics are not appropriate for prophylactic use in patients with VUR but cotrimoxazole remains the preferred prophylactic agent for VUR. [11]

There are even studies that argue that prophylactic antibiotic usage is not indicated, regardless of the severity of hydronephrosis, as the risk of UTI is minimal in this population. [12, 13]

In the clinical practice, our management of these patients is oriented according to the degree of VUR detected at VCUG, family and personal compliance and the recurrence of UTIs (Fig.1). We use antibiotic propylaxis  according to ISPN guidelines’ indications.

 

Figure 1. VUR patients’ management flow-chart.  VUS= voiding urosonography

References

1)  “Managing urinary tract infections”-  Sermin A. Saadeh & Tej K. Mattoo  - Pediatr Nephrol (2011) 26:1967–1976

2)  “Urinary tract infection in children diagnosis, treatment and long-term management” - National Institute for Health and Clinical Excellence (NICE), 2007 -  Clinical Guideline

3)  “Pediatric Urinary Tract Infection” - Author: Donna J Fisher, MD; Chief Editor: Russell W Steele, MD - Medscape - Drugs, Disease and Procedures – May 2011

4)  “Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up” - Anita Ammenti, Luigi Cataldi, Roberto Chimenz, Vassilios Fanos, Angela La Manna, Giuseppina Marra, Marco Materassi, Paolo Pecile, Marco Pennesi, Lorena Pisanello, Felice Sica, Antonella Toffolo, Giovanni Montini - Acta Pædiatrica, November 2011

5)  What do the latest guidelines tell us about UTIs in children under 2 years of age” - Kjell Tullus - Pediatr Nephrol (2012) 27:509–511

6)  Antibiotics for treating lower urinary tract infection in children (Review)” - Fitzgerald A, Mori R, Lakhanpaul M, Tullus K - Copyright © 2012 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd

7)  Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months” - Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management - Pediatrics 2011;128;595; originally published online August 28, 2011

8)  “Long-term clinical consequences of urinary tract infections during childhood: a review” - Antonella Toffolo, Anita Ammenti, Giovanni Montini - Acta Pædiatrica ISSN 0803–5253, July 2012

9)  “Diagnosis of vesicoureteral reflux with ultrasonography” - Darge K. - Pediatr Nephrol. 2002 Jan;17 (1):52-60.

10)  “Different Guidelines for Imaging After First UTI in Febrile Infants: Yield, Cost, and Radiation” - Claudio La Scola, Chiara De Mutiis, Ian K. Hewitt, Giuseppe Puccio, Antonella Toffolo, Pietro Zucchetta, Francesca Mencarelli, Martino Marsciani, Roberto Dall'Amico and Giovanni Montini - Pediatrics 2013;131;e665

11)  “Antibiotic resistance patterns of community-acquired urinary tract infections in children with vesicoureteral reflux receiving prophylactic antibiotic therapy.” - Cheng CH, Tsai MH, Huang YC, Su LH, Tsau YK, Lin CJ, Chiu CH, Lin TY. - Pediatrics. 2008 Dec

12)  “Antenatal hydronephrosis: infants with minor postnatal dilatation do not need prophylaxis.” - Lidefelt KJ, Herthelius M. - Pediatr Nephrol. 2008 Nov;23 (11):2021-4. Epub 2008 Jun 17.

13)  “Probability of urinary tract infection in infants with ureteropelvic junction obstruction: is antibacterial prophylaxis really needed?” - Ali Islek, Ayfer Gür Güven, Mustafa Koyun Pediatric Nephrology  Volume 26, Number 10, Pediatr Nephrol. 2011 Oct;26 (10):1837-41. Epub 2011 Apr 26

14)  “Vesicoureteral reflux: comparison between urosonography and radionuclide” – Ascenti G., Zimbaro G., Mazziotti S., Chimenz R., Baldari S., Fede C. - Pediatr Nephrol. 2003 Aug;18 (8):768-71. Epub 2003 Jun 11

15)  Harmonic US imaging of vesicoureteric reflux in children: usefulness of a second generation US contrast agent.” - Ascenti G, Zimbaro G, Mazziotti S, Chimenz R, Fede C, Visalli C, Scribano E. - Pediatr Radiol. 2004 Jun;34 (6):481-7. Epub 2004 Apr 24

16)  Pleiotropismo genetico-immunologico nella risposta all'infezione da EBV” – Carmelo Salpietro et. Al - Italian Journal of Genetic and Pediatric Immunology, Anno IV numero 1 - gennaio 2013 

17)  Genetic polymorphisms in Toll-like receptors among pediatric patients with renal parenchymal infections of different clinical severities” - Cheng CH, Lee YS, Chang CJ, Lin TY. -  PLoS One. 2013;8 (3):e58687

18)  “Urinary tract infections in children: microbial virulence versus host susceptibility” - Svanborg C. - Adv Exp Med Biol. 2013;764:205-10.

 

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