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Update on Childhood Urinary Tract Infection and Vesicoureteral Reflux
Update on Childhood Urinary Tract Infection and Vesicoureteral Reflux Lorraine E. Bell, MDCM,* and Tej K. Mattoo, MD, DCH, FRCP (UK)† Summary: Urinary tract infection (UTI) is a leading cause of serious bacterial infection in young children. Vesicoureteral reflux (VUR), a common pediatric urologic disorder, is believed to predispose to UTI, and both are associated with renal scarring. The complex interaction of bacterial virulence factors and host defense mechanisms influence renal damage. However, some renal parenchymal abnormalities associated with VUR are noninfectious in origin. Long-term, renal parenchymal injury may be associated with hypertension, pregnancy complications, proteinuria, and renal insufficiency. Optimal management of VUR and UTI is controversial because of the paucity of appropriate randomized controlled trials; there is a need for well-designed studies. The recently launched Randomized Intervention for children with VesicoUreteral Reflux (RIVUR) study hopefully will provide insight into the role of antimicrobial prophylaxis of UTI in children with VUR. Semin Nephrol 29:349-359 © 2009 Elsevier Inc. All rights reserved. Keywords: Urinary tract infection, vesicoureteral reflux, antimicrobial prophylaxis, chronic kidney disease
rinary tract infection (UTI) is a leading cause of serious bacterial illness in febrile infants, afflicting at least 7% of those younger than 6 months of age and 5% of those 6 to 24 months of age.1 Throughout childhood the cumulative incidence is approximately 10% in girls and 3% in boys. Vesicoureteral reflux (VUR) is diagnosed most frequently after UTI, particularly in newborns and infants (36%-49% of cases), and in girls of all ages. At younger than 6 months of age no difference in the incidence between boys and girls is noted.2 Some cases of VUR are discovered because of antenatal hydronephrosis or through sibling screening. VUR is less common and less severe in African American children, compared with Caucasian children.3
U
*Department of Pediatrics, Division of Pediatric Nephrology, McGill University Health Centre, Montreal, Quebec, Canada. †Division of Pediatric Nephrology & Hypertension, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI. Dr. Mattoo is supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Address reprint requests to Tej K. Mattoo, MD, DCH, FRCP (UK), Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2009.03.011
Seminars in Nephrology, Vol 29, No 4, July 2009, pp 349-359
UTI
Pathogenesis Urinary infection usually is ascending, with inoculation of fecally derived organisms from the urethra and peri-urethral tissues into the bladder.4 The most prevalent pathogens in several recent pediatric studies were Escherichia coli (54%-67%), Klebsiella (6%-17%), Proteus (5%12%), Enterococcus (3%-9%) and Pseudomonas (2%-6%).5-7 Previously, E coli accounted for 80% to 90% of infections, and it is not clear if the change in frequency was caused by sampling bias (not all infections cultured) or a result of increasing antibiotic use. Among patients with urinary tract anomalies or impaired immune systems, less-virulent organisms, such as Staphylococcus epidermidis, Haemophilus influenzae, and group B Streptococcus, may be responsible. The hematogenous route of infection is far less common with generally different causal organisms, such as Staphylococcus aureus, Candida, and Salmonella; Pseudomonas aeruginosa and Proteus can infect by either route. Risk factors include obstruction and trauma. 349
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Bacterial Pathogenetic Factors The fimbriae of gram-negative bacteria adhere to urinary mucosal receptors, facilitating colonization and entry into host urothelial cells. Adherence also may impair the flushing action of urine flow.8 Fimbriae of uropathogenic E coli (UPEC) pilfer host iron, an essential metabolic factor, and secrete toxins. Cytotoxic necrotizing factor 1 and ␣-hemolysin, encoded by approximately 50% of UPEC, are associated with increased clinical severity.9 The toxins inflict extensive tissue damage, facilitate bacterial dissemination and release of host nutrients, and disable host immune effector cells.9 UPEC also can replicate within the urothelium, forming intracellular bacterial communities; these are protected from antibiotics and probably the host immune system, and may seed recurrent infection.10
Urothelium Defense Mechanisms and Inflammatory Response The normal bladder can clear itself of bacteria within 2 to 3 days through antibacterial properties of urine and its constituents, intrinsic mucosal defense mechanisms, and elimination by voiding.4 Locally produced urinary proteins may trap bacteria or interfere with their ability to adhere (eg, mucin and Tamm Horsfall protein, respectively).11 Clearing is impaired by inadequate micturition, frank residual urine, increased bladder pressure, bladder mucosa inflammation, or stones. Once attached, bacterial recognition by urothelial Toll-like receptors incites production of antimicrobial proteins (defensins), chemokines, and cytokines, including interleukin (IL)-1, tumor necrosis factor-␣, IL-6, and IL-8, leading to inflammatory cell recruitment. With microbial invasion of the kidney (pyelonephritis), acute and generally focal inflammatory cell infiltrates of the pelvic mucosa (pyelitis) and renal interstitium (nephritis) occur, accompanied by edema, tubular cell damage, and sometimes necrosis.4,12 Numerous elements may contribute to renal tissue damage, including specific bacterial virulence factors and the host inflammatory response.13 Genetic variability in infection response may influence disease severity and susceptibility to scarring.
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For example, IL-8 receptor (CXCR1) gene sequence variants and diminished expression recently were identified in UTI-prone children.14 It has been speculated that children with increased IL-8 responses have more pronounced symptoms of infection, leading to earlier diagnosis, improved bacterial clearance, and reduced risk of permanent cell damage.13 Renal injury after UTI results primarily from the host inflammatory response. Antibiotics significantly decrease urinary levels of IL-1, IL-6, and IL-8 as early as 12 to 24 hours after beginning treatment for febrile UTI, supporting the notion that early treatment (within 72 hours) is important to prevent renal scarring.13 CLINICAL PRESENTATION Young infants often present with fever alone (ⱖ38°C); irritability, vomiting, lethargy, or poor feeding variably may be present. For those younger than 3 months there is an increased risk of bacteremia and a greater possibility of undiagnosed congenital urologic malformations.15 Older children generally have more explicit symptoms of bladder inflammation and/or flank pain. A recent meta-analysis evaluated the diagnostic accuracy of UTI signs and symptoms in infants (3-24 mo) with fever (ⱖ38°C), and in verbal children (⬎24 mo) presenting with urinary or abdominal symptoms.16 For infants, any of the following increased the positive likelihood ratio (L) of UTI to 2 or more: history of prior UTI, fever of more than 24 hours’ duration or higher than 40°C, absence of circumcision in males, and suprapubic tenderness. Combinations of these findings amplified probability. For verbal children, the following symptoms were most reliable: abdominal pain with fever higher than 38°C (LR, 6.3; 95% confidence interval [CI], 2.5-16), back pain (LR, 3.6; 95% CI, 2.1-6.1), new-onset urinary incontinence (LR, 4.6; 95% CI, 2.8-7.6), dysuria (LR, 2.4; 95% CI, 1.8-3.1), and frequency (LR, 2.8; 95% CI, 2-4). Offensive urine odor was not predictive.16 DIAGNOSIS OF UTI
Specimen Collection A noncontaminated urine sample is fundamental. For infants and non–toilet-trained children,
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Table 1. Screening Urinalysis: Diagnostic Criteria for Urinary Tract Infection
True-Positive Rate (Sensitivity) Test and Positivity Criterion Dipstick Any nitrite only Any LE only Any nitrite or LE Both nitrite and LE Microscopy Gram stain any organisms Centrifuged urine ⱖ5 WBC/hpf Uncentrifuged urine ⱖ10 WBC/mm3 Enhanced U/A ⱖ10 WBC/mm3 plus GS⫹ Enhanced U/A ⱖ10 WBC/mm3 or GS⫹
No. of Summary Studies Estimate
False-Positive Rate (1-Specificity)
Range
Summary Estimate
Range
13 7 9 5
0.50 0.83 0.88 0.72
0.16-0.72 0.64-0.89 0.71-1.0 0.14-0.83
0.02 0.16 0.07 0.04
0-0.05 0.05-0.29 0.02-0.24 0-0.05
5 5 9 2 2
0.93 0.67 0.77 0.85 0.95
0.80-0.98 0.55-0.88 0.57-0.92 0.75-0.88 0.94-0.96
0.05 0.21 0.11 0.01 0.11
0-0.13 0.16-0.23 0.05-0.63 0.01 0.07-0.16
Abbreviations: GS, gram stain; hpf, high-power field; LE, leukocyte esterase; U/A, urinalysis; WBC, white blood cell. Adapted with permission from Pediatrics, Vol. 104, Page e54, Copyright © 1999 by the AAP.20
the most accurate method of collection is suprapubic bladder aspiration, however, it rarely is practical. Urethral catheterization or spontaneously voided clean midstream samples (usually obtained while disinfecting for catheterization or suprapubic bladder aspiration) are the most reliable alternatives. Perineal urine bag collection has a high rate of contamination and should be avoided for culture, but may help in screening infants older than 3 months for suprapubic bladder aspiration or urethral catheterization.17 For toilet-trained children, appropriate cleansing of the perineal/genital area before midstream urine collection is essential.18,19 This may be facilitated for girls by having them sit backward on the toilet seat.
Urinalysis Although urine culture is the gold standard for UTI diagnosis, more rapid screening may be required for preliminary clinical decision making. Urine Gram stain is the single most sensitive and specific test.20,21 Enhanced urinalysis (unspun urine hemocytometer white blood cell count and Gram stain) further improves sensitivity and specificity (Table 1).20,22 Microscopy of centrifuged urine for white blood cells per high-power field is inadequate. For older infants and children, urine dipstick testing for both
leukocyte esterase and nitrites may be used if microscopy is unavailable, however, urine still must be sent for culture and symptomatic children must be treated pending the results because the dipstick false-negative rate is significant (Table 1).20 Failure to diagnose and promptly treat a UTI because of a false-negative test is generally a greater risk than that of a brief provisional course of therapy for a false-positive result.
Urine Culture Bacterial colony count criteria to distinguish urine infection from contamination are operational, not absolute.23 Although 105 colony forming units (CFU) per mL (108 CFU/L) is the generally accepted diagnostic cut-off level for midstream urine samples, true infection with a lower colony count occurs (eg, reduced bladder incubation time owing to urinary frequency or high urine flow rate, presence of an antibacterial agent in the urine).23 Table 2 illustrates suggested CFU criteria for UTI diagnosis in children based on 8 publications.24 Some investigators recently proposed a threshold of greater than 5 ⫻ 104 CFU/mL for catheterized specimens,25 however, this view is far from universal; other investigators recommend a lower value, such as 104 CFU/mL, particularly in the
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Table 2. Urine Culture: Diagnostic Criteria for Urinary Tract Infection
Urine Collection Technique
CFU/mL (pure growth)
Probability of Infection
Suprapubic aspiration
Gram negative rod, any Gram positive cocci, more than a few thousand
⬎99% ⬎99%
Catheterization
⬎105 104-105 103-104
95% Likely Suspicious
Clean void (male)
⬎104
Likely
Clean void (female)
3 samples ⬎105 2 samples ⬎105 1 sample ⬎105 5 ⫻ 104-105 104-5 ⫻ 104
95% 90% 80% Suspicious Suspicious if symptomatic
Adapted from Hellerstein.24
presence of pyuria or symptoms suggestive of UTI.23,26 TREATMENT
Infants Younger Than 3 Months All febrile neonates should be treated with intravenous antibiotics pending urine, blood, and cerebrospinal fluid culture results. For infants older than 1 month but younger than 3 months of age with suspected or confirmed UTI, intravenous antibiotics are recommended after appropriate cultures (blood, urine, ⫾ cerebrospinal fluid). There have been no large prospective studies of outpatient management in this age group.27
Pyelonephritis: Infants Older Than 3 Months and Children A 2007 Cochrane Review concluded that 10 to 14 days of oral treatment with cefixime, ceftibuten, or amoxicillin/clavulanic acid was as effective as 2 to 4 days of intravenous therapy followed by oral, to complete 7 to 21 days of antibiotic treatment. Predominantly third- and fourth-generation cephalosporins were studied, therefore generalizability of results is limited. There were inadequate data to determine the optimal total duration. Single daily aminoglycoside dosing was as safe and effective as 8-hourly dosing.28 Because
antibiotic resistance patterns vary by geographic region and organism, awareness of local data is essential for initial empiric therapy. Final antibiotic choice should be based on culture and sensitivity results. Recently published pediatric data from North America and Europe show significant antimicrobial resistance rates for E coli: ampicillin (38%-65%), amoxicillin/clavulanic acid (7%-43%), and cotrimoxazole (8%-35%).5-7,29 Klebsiella and Proteus antibiotic resistance was similarly high, whereas their sensitivity to cefixime, ceftriaxone, and aminoglycosides generally was maintained. A recent study showed increased symptomatic relapse with ceftibuten compared with cotrimoxazole, possibly because -lactam antibiotics fail to eradicate uropathogens from the vaginal or intestinal microflora.30 Most studies of oral therapy excluded patients with major uropathology and were not stratified for the presence of dilating vesicoureteral reflux, so the results cannot be generalized to these children. Prompt antimicrobial therapy generally is believed necessary to diminish risk of renal scarring,31,32 however, 2 recent reports question this notion. A post hoc subgroup analysis of a pyelonephritis-oral antibiotic therapy study found no increase in scarring on dimercaptosuccinic acid (DMSA) scan for those treated late versus early.33,34 Patients excluded from their
Urinary tract infection and reflux
analysis were those who were most ill (severe clinical sepsis, dehydration, vomiting, or increased serum creatinine level).34 It is conceivable that the patients who presented later had less severe renal inflammation and were inherently at lower risk. Findings by Doganis et al35 were similar, but 50% of their study patients were lost to follow-up evaluation. Given the limitations of these studies, it seems prudent to err on the side of caution and not delay diagnostic evaluation or therapy.
Lower Urinary Tract Infection: Older Infants and Children A 2003 Cochrane Review found that most studies addressing short versus standard-duration oral antibiotic therapy for lower UTIs were of inferior quality.36 However, consensus opinions are that short-course (2-4 days) treatment for uncomplicated cystitis likely is effective.36,37 An adequately powered, well-designed, randomized, controlled trial is indicated. Short-course treatment recommendations are not for children with urinary tract pathology. UTI RECURRENCE Recurrent UTIs develop in approximately 75% of children whose first infection occurs before the age of 1 year, and in about 40% of girls and 30% of boys presenting after this age.37 Most studies of features predicting recurrence have important limitations.37 Risk factors identified include dilating VUR, family history of UTI, infrequent voiding, and inadequate fluid ingestion. Strategies that may help prevent recurrence include management of voiding dysfunction and increased fluid intake. The role of antibiotics is controversial and evidence weak; well-designed, randomized, controlled studies are lacking.38 LONG-TERM OUTCOME Approximately 70% of infants and children with their first febrile UTI have pyelonephritis39,40 and renal scars may follow in 15% to 30%.33,41 With timely appropriate therapy most infants and children recover promptly without major long-term sequelae, but a small number are at risk for significant morbidity, progressive renal damage, and renal insufficiency. Included are
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those with urologic abnormalities, dysplasia, and recurrent pyelonephritis.37 COVERT BACTIURIA Covert bactiuria (asymptomatic colonization of the urinary tract) is often an incidental finding during screening or follow-up evaluation after treatment of symptomatic UTI. If it is ascertained that the infant or child is truly symptom free, has a normal physical examination, normal voiding pattern, no impairment of renal function, and no anomalies on renal imaging, antibiotic therapy should be avoided.32 E coli strains causing asymptomatic bactiuria have evolved to persist for months to years in a commensal-like relationship with the host urinary tract and possibly protect it from colonization by more pathogenic UPEC.9 Elimination of these potentially protective bacteria may increase the risk of acute pyelonephritis. VUR AND REFLUX NEPHROPATHY VUR is a frequent pediatric urologic disorder affecting 1% to 2% of otherwise normal children.42 VUR is believed to predispose to UTI, and the two are linked with renal scarring. In 1960, Hodson and Edwards43 associated VUR with chronic pyelonephritis, which subsequently came to be known as reflux nephropathy.44 After acute pyelonephritis, renal scarring visible on intravenous urography takes about 1 to 2 years to develop, but is seen much earlier on DMSA.45,46 The International Reflux Study reported that renal injury is more frequent in children younger than 2 years old, particularly if VUR is high grade.47 Besides younger age, other factors that increase the probability of renal scarring in children with VUR and UTI include delayed treatment of UTI, recurrent UTI, higher grades of VUR, bacterial virulence, and possibly genetic factors such as angiotensin converting enzyme gene polymorphism.48-52 Renal scarring may occur in the absence of VUR and without UTI.53 In addition, the renal imaging abnormalities often referred to as renal scarring actually may represent congenital renal dysplasia in some patients. This is supported by renal imaging changes in infants and
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children with VUR but no history of UTI, as in infants with VUR diagnosed during postnatal follow-up evaluation for antenatal hydronephrosis and in siblings of index patients with VUR.54-56
Role of Voiding Dysfunction and Constipation VUR may be associated with voiding dysfunction or dysfunctional elimination syndrome, an abnormal pattern of elimination characterized by bowel and bladder incontinence and withholding, generally without underlying anatomic or neurologic abnormalities.57 Voiding dysfunction may predispose to recurrent UTI, induce and perpetuate VUR, adversely affect the results of ureteral reimplantation, and result in permanent renal damage.58-60 Constipation may increase the risk of recurrent UTI in children with VUR, as well as the likelihood of urinary incontinence, bladder overactivity, dyscoordinated voiding, and deterioration of VUR.61 Constipation causes compression of the bladder and bladder neck, resulting in increased bladder storage pressure and postvoid residual urine volume. The distended colon and/or soiling also provide a reservoir of pathogens.62-64
Complications of Reflux Nephropathy Reflux nephropathy has been reported to be responsible for 12% to 21% of all children with chronic renal failure.65,66 According to the North American Pediatric Renal Trials and Collaborative Studies 2006 Annual Report, 536 (8.4%) of the 6,405 children with chronic renal insufficiency had reflux nephropathy, which, according to the registry, is the fourth most common cause of chronic renal insufficiency after obstructive uropathy, renal aplasia/hypoplasia/dysplasia, and focal segmental glomerulosclerosis.67 However, in databases following up chronic kidney disease, dialysis, and transplant patients, labeling all those with renal imaging abnormalities and a past history of UTI or VUR as having chronic pyelonephritis or reflux nephropathy has lead to overestimation of the contribution of UTI and/or VUR to end-stage renal disease, and underestimation of the frequency of renal dysplasia.
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Hypertension has been reported to occur in 9% to 30% of children and young adults with renal scarring and it may take years to develop.68 It is believed to be caused by segmental ischemia with increased renin secretion and does not depend consistently on the severity of the scarring.68,69 In a study that involved blood pressure recording in 664 patients diagnosed with VUR between 1970 and 2004, there were 20 (3%) patients who developed hypertension.70 The estimated probability of hypertension was 2% at 10 years of age, 6% at 15 years of age, and 15% at 21 years of age. The survival analysis revealed that about 50% of children with unilateral and bilateral renal damage develop persistent hypertension at about 30 and 22 years of age, respectively. The presence of hypertension correlated strongly with the renal damage at entry.70 In a study on otherwise healthy children referred to a hypertension clinic, 33 (21%) of 159 patients were found to have renal scarring.71 The etiology of scarring in these patients was not studied and could have been caused by reasons other than UTI and/or VUR. Renal parenchymal injury may be associated with proteinuria, and in some cases nephrotic syndrome. Focal segmental glomerulosclerosis is known to occur in patients with reflux nephropathy.72 The suggested pathogenesis is glomerular hyperfiltration in remnant nephrons with modifications in permselectivity to macromolecules such as albumin and progression of renal disease.73,74 In a study in children having bilateral VUR with renal scarring and normal creatinine clearance, microalbuminuria was detected in 53.5% of the cases.74 Renal scarring also may cause pregnancy-related complications such as recurrent pyelonephritis, toxemia or pregnancy, low-birth-weight babies, and miscarriage.75-79 An increased risk of nephrolithiasis also has been reported in children with VUR.80
Management of VUR Primary VUR generally improves with time, particularly when the following factors are present: non-white race, lower reflux grade, absence of renal damage, and lack of voiding dysfunction.81 The traditional management has
Urinary tract infection and reflux
included prompt treatment of UTI and longterm antimicrobial prophylaxis until the resolution of VUR. Surgical intervention has been advocated in those with high-grade VUR, recurrent UTI despite antimicrobial prophylaxis, or noncompliance with medical management.
Antimicrobial prophylaxis A number of reports have raised serious doubts about the relevance of long-term antimicrobial prophylaxis for renal injury prevention in patients with VUR.82-84 Three systematic reviews have concluded the following: many published studies on antibiotic prophylaxis have been poorly designed with biases known to overestimate the true treatment effect.85 It is uncertain whether antibiotic prophylaxis or surgical treatment of primary VUR in children confers any clinically important benefit.86 VUR is a weak predictor of renal parenchymal damage in children hospitalized with febrile UTI.87 Some recent studies compared surveillance only with antibiotic prophylaxis in children with primary VUR, the end points for the studies being the frequency of UTI and/or renal scarring. No significant difference between the 2 groups was reported.88-90 The observations reported in these studies are important but are limited by a number of factors that include the number of patients studied, ages of the patients included in the study, lack of blindness, and urine collection methods in non–toilet-trained children.
Surgical intervention The decision for surgical intervention in VUR depends on multiple factors that include patient age, renal function, duration of follow-up period, and VUR grade. VUR grade V has the lowest rate of spontaneous resolution, particularly in older children, and some advise surgical intervention if there is no improvement within a year, particularly with recurrent infections on antimicrobial prophylaxis.84,91,92 Minimally invasive procedures include endoscopic injection of a bulking agent (Deflux; Q Med Scandinavia Inc., Princeton, NJ) at the ureterovesical junction, trigonoplasty,93 the use of small inguinal incisions for an extravesical surgical approach,94 or laparoscopic ureteral reimplantation.95 A meta-analysis of all of the endoscopic
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modalities used for management of VUR suggests rates of cure per ureter for grades I and II of 78.5%, grade III of 72%, grade IV of 63%, and grade V of 51%.96 The most commonly performed open technique (Cohen Cross trigonal reimplantation) remains the gold standard for the correction of VUR with a success rate of 97% to 99%.97 CONCLUSIONS The recent knowledge about UTI and VUR, and controversies regarding the extent of their role in renal scarring, has generated much interest among clinicians as well as researchers. The consequences of delayed versus early treatment of acute febrile UTI and the appropriateness of medical versus surgical versus no intervention for various grades of VUR will continue to be debated until more prospective, randomized, and preferably blinded and placebo-controlled studies are performed to confirm or refute these observations. One such study that started recruiting patients in 2007 is the Randomized Intervention for children with VesicoUreteral Reflux (RIVUR) study, which will evaluate the role of antimicrobial prophylaxis in children with grades I to IV VUR diagnosed after febrile UTI. In the meantime, it is advisable that VUR and UTI be considered risk factors for renal scarring and that each patient is treated with caution. REFERENCES 1. 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. 2. Chen JJ, Pugach J, West D, Naseer S, Steinhardt GF. Infant vesicoureteral reflux: a comparison between patients presenting with a prenatal diagnosis and those presenting with a urinary tract infection. Urology. 2003;61:442-6. 3. Chand DH, Rhoades T, Poe SA, Kraus S, Strife CF. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. J Urol. 2003;170:1548-50. 4. Tolkoff-Rubin NE, Cotran RS, Rubin RH. Urinary tract infection, pyelonephritis, and reflux nephropathy. In: Brenner BM, editor. Brenner & Rector’s the kidney. Philadelphia: Saunders Elsevier; 2007. p. 1203-38. 5. Gokce I, Alpay H, Biyikli N, Ozdemir N. Urinary tract pathogens and their antimicrobial resistance patterns in Turkish children. Pediatr Nephrol. 2006;21:1327-8.
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6. Prelog M, Schiefecker D, Fille M, Wurzner R, Brunner A, Zimmerhackl LB. Febrile urinary tract infection in children: ampicillin and trimethoprim insufficient as empirical mono-therapy. Pediatr Nephrol. 2008;23: 597-602. 7. Zhanel GG, Hisanaga TL, Laing NM, DeCorby MR, Nichol KA, Palatnick LP, et al. Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents. 2005; 26:380-8. 8. Johnson JR. Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am. 2003;17:261-78. 9. Wiles TJ, Kulesus RR, Mulvey MA. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp Mol Pathol. 2008;85:11-9. 10. Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med/ Public Library of Science. 2007 [cited 2008 November 10];4:e329. Available from: http://www.plos.org/ journals/. 11. Chowdhury P, Sacks SH, Sheerin NS. Minireview: functions of the renal tract epithelium in coordinating the innate immune response to infection. Kidney Int. 2004;66:1334-44. 12. Weiss M, Liapis H, Tomaszewski JE, Arend LJ. Pyelonephritis and other infections, reflux nephropathy, hydronephrosis, and nephrolithiasis. In: Jennette CJ, Olson JL, Schwartz MM, Silva FG, editors. Hepinstall’s pathology of the kidney. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 991-1081. 13. Jahnukainen T, Chen M, Celsi G. Mechanisms of renal damage owing to infection. Pediatr Nephrol. 2005; 20:1043-53. 14. Lundstedt AC, McCarthy S, Gustafsson MCU, Godaly G, Jodal U, Karpman D, et al. A genetic basis of susceptibility to acute pyelonephritis. PLoS ONE. 2007 [cited 2008 November 10];2:e825. Available from: http://www.plos.org/journals/. 15. National Collaborating Centre for Women’s and Children’s Health. Feverish illness in children—assessment and initial management in children younger than 5 years. In: Welsh A, editor. CG47. National Institute for Health and Clinical Excellence: clinical guidelines. London, RCOG Press; 2007. Available from: http://www. nice.org.uk/nicemedia/pdf/CG47Guidance.pdf [accessed June 23, 2009]. 16. Shaikh N, Morone NE, Lopez J, Chianese J, Sangvai S, D’Amico F, et al. Does this child have a urinary tract infection? JAMA. 2007;298:2895-904. 17. McGillivray D, Mok E, Mulrooney E, Kramer MS. A head-to-head comparison: “clean-void” bag versus catheter urinalysis in the diagnosis of urinary tract infection in young children. J Pediatrics. 2005;147: 451-6. 18. Vaillancourt S, McGillivray D, Zhang X, Kramer MS. To clean or not to clean: effect on contamination
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from the Italian Renal Infection Study Trials. Pediatrics. 2008;122:486-90. Montini G, Toffolo A, Zucchetta P, Dall’Amico R, Gobber D, Calderan A, et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ. 2007;335:386. Doganis D, Siafas K, Mavrikou M, Issaris G, Martirosova A, Perperidis G, et al. Does early treatment of urinary tract infection prevent renal damage? Pediatrics. 2007 [cited 2008 November 10];120:e922-e928. Available from: http://pediatrics.aappublications.org. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database Syst Rev. 2003;1:CD003966. National Institute for Health and Clinical Excellence. Urinary tract infection: diagnosis, treatment and longterm management of urinary tract infection in children. CG54, i-136. London: National Institute for Health and Clinical Excellence, 2007. Williams GJ, Wei L, Lee A, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev. 2006; 4:CD001534. Benador D, Benador N, Slosman DO, Nussl D, Mermillod B, Girardin E. Cortical scintigraphy in the evaluation of renal parenchymal changes in children with pyelonephritis. J Pediatr. 1994;124:17-20. Lin KY, Chiu NT, Chen MJ, Lai CH, Huang JJ, Wang YT, et al. Acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract infection. Pediatr Nephrol. 2003;18:362-5. Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M, et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104:79-86. Gargollo PC, Diamond DA. Therapy insight: what nephrologists need to know about primary vesicoureteral reflux. Nat Clin Pract Nephrol. 2007;3:551-63. Hodson CJ, Edwards D. Chronic pyelonephritis and vesico-ureteric reflex. Clin Radiol. 1960;11:219-31. Bailey RR. The relationship of vesico-ureteric reflux to urinary tract infection and chronic pyelonephritis-reflux nephropathy. Clin Nephrol. 1973;1:13241. Filly R, Friedland GW, Govan DE, Fair WR, Filly R, Friedland GW, et al. Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology. 1974;113:145-53. Goldraich NP, Goldraich IH. Update on dimercaptosuccinic acid renal scanning in children with urinary tract infection. Pediatr Nephrol. 1995;9:221-6. Piepsz A, Tamminen-Mobius T, Reiners C, Heikkila J, Kivisaari A, Nilsson NJ, et al. Five-year study of medical or surgical treatment in children with severe vesicoureteral reflux dimercaptosuccinic acid findings. International Reflux Study Group in Europe. Eur J Pediatr. 1998;157:753-8. Hohenfellner K, Hunley TE, Brezinska R, Brodhag P,
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Shyr Y, Brenner W, et al. ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol. 1999;13:514-8. Jakobsson B, Berg U, Svensson L. Renal scarring after acute pyelonephritis. Arch Dis Child. 1994;70:111-5. Jodal U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am. 1987;1:713-29. Lomberg H, Hellstrom M, Jodal U, Leffler H, Lincoln K, Svanborg EC. Virulence-associated traits in Escherichia coli causing first and recurrent episodes of urinary tract infection in children with or without vesicoureteral reflux. J Infect Dis. 1984;150:561-9. Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, et al. Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis. 1999;34:140-5. Ditchfield MR, de Campo JF, Nolan TM, Cook DJ, Grimwood K, Powell HR, et al. Risk factors in the development of early renal cortical defects in children with urinary tract infection. AJR Am J Roentgenol. 1994;162:1393-7. Hiraoka M, Hori C, Tsukahara H, Kasuga K, Ishihara Y, Sudo M. Congenitally small kidneys with reflux as a common cause of nephropathy in boys. Kidney Int. 1997;52:811-6. Noe HN. The long-term results of prospective sibling reflux screening. J Urol. 1992;148:1739-42. Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary vesicoureteric reflux in male and female infants with prenatal hydronephrosis. Br J Urol. 1997;80:319-27. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998;160:1019-22. Koff SA. Relationship between dysfunctional voiding and reflux. J Urol. 1992;148:1703-5. Seruca H. Vesicoureteral reflux and voiding dysfunction: a prospective study. J Urol. 1989;142:494-8. van Gool JD, Hjalmas K, Tamminen-Mobius T, Olbing H. Historical clues to the complex of dysfunctional voiding, urinary tract infection and vesicoureteral reflux. The International Reflux Study in Children. J Urol. 1992;148:1699-702. Chase JW, Homsy Y, Siggaard C, Sit F, Bower WF. Functional constipation in children. J Urol. 2004;171: 2641-3. Neumann PZ, DeDomenico IJ, Nogrady MB. Constipation and urinary tract infection. Pediatrics. 1973; 52:241-5. O’Regan S, Yazbeck S, Schick E. Constipation, bladder instability, urinary tract infection syndrome. Clin Nephrol. 1985;23:152-4. Rushton HG. Wetting and functional voiding disorders. Urol Clin North Am. 1995;22:75-93. Chantler C, Carter JE, Bewick M, Counahan R, Cameron JS, Ogg CS, et al. 10 years’ experience with
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regular haemodialysis and renal transplantation. Arch Dis Child. 1980;55:435-45. Deleau J, Andre JL, Briancon S, Musse JP, Deleau J, Andre JL, et al. Chronic renal failure in children: an epidemiological survey in Lorraine (France) 1975-1990. Pediatr Nephrol. 1994;8:472-6. 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. JAMA. 2007;298:179-86. Wennerstrom M. Ambulatory blood pressure 16-26 years after the first urinary tract infection in childhood. J Hypertens. 2000;18:485-91. Stecker JF Jr, Read BP, Poutasse EF. Pediatric hypertension as a delayed sequela of reflux-induced chronic pyelonephritis. J Urol. 1977;118:644-6. Silva J, Santos Diniz J, Marino V, Lima E, Cardoso L, Vasconcelos M, et al. Clinical course of 735 children and adolescents with primary vesicoureteral reflux. Pediatr Nephrol. 2006;21:981-8. Ahmed M, Eggleston D, Kapur G, Jain A, Valentini RP, Mattoo TK. Dimercaptosuccinic acid (DMSA) renal scan in the evaluation of hypertension in children. Pediatr Nephrol. 2008;23:435-8. Morita M, Yoshiara S, White RH, Raafat F. The glomerular changes in children with reflux nephropathy. J Pathol. 1990;162:245-53. Bhathena DB, Weiss JH, Holland NH, McMorrow RG, Curtis JJ, Lucas BA, et al. Focal and segmental glomerular sclerosis in reflux nephropathy. Am J Med. 1980; 68:886-92. Coppo R, Porcellini MG, Gianoglio B, Alessi D, Peruzzi L, Amore A, et al. Glomerular permselectivity to macromolecules in reflux nephropathy: microalbuminuria during acute hyperfiltration due to aminoacid infusion. Clin Nephrol. 1993;40:299-307. el-Khatib M, Packham DK, Becker GJ, Kincaid-Smith P, el-Khatib M, Packham DK, et al. Pregnancy-related complications in women with reflux nephropathy. Clin Nephrol. 1994;41:50-5. Jacobson SH, Eklof O, Eriksson CG, Lins LE, Tidgren B, Winberg J. Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ. 1989;299:703-6. Jungers P, Houillier P, Chauveau D, Choukroun G, Moynot A, Skhiri H, et al. Pregnancy in women with reflux nephropathy. Kidney Int. 1996;50:593-9. Mansfield JT, Snow BW, Cartwright PC, Wadsworth K. Complications of pregnancy in women after childhood reimplantation for vesicoureteral reflux: an update with 25 years of follow-up. J Urol. 1995;154: 787-90. Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. 1998;12:727-36. Roberts JP, Atwell JD. Vesicoureteric reflux and urinary calculi in children. Br J Urol. 1989;64:10-2. Silva JM, Diniz JS, Lima EM, Vergara RM, Oliveira EA.
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Predictive factors of resolution of primary vesicoureteric reflux: a multivariate analysis. BJU Int. 2006; 97:1063-8. Arant BS. Medical management of mild and moderate vesicoureteral reflux: followup studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group. J Urol. 1992;148: 1683-7. Cooper CS, Chung BI, Kirsch AJ, Canning DA, Snyder IHM. The outcome of stopping prophylactic antibiotics in older children with vesicoureteral reflux. J Urol. 2000;163:269-73. Tamminen-Mobius T, Brunier E, Ebel KD, Lebowitz R, Olbing H, Seppanen U, et al. Cessation of vesicoureteral reflux for 5 years in infants and children allocated to medical treatment. The International Reflux Study in Children. J Urol. 1992;148:1662-6. Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr. 2001;138:868-74. Wheeler D, Vimalachandra D, Hodson EM, Roy LP, Smith G, Craig JC. Antibiotics and surgery for vesicoureteric reflux: a meta-analysis of randomised controlled trials. Arch Dis Child. 2003;88:688-94. Gordon I, Barkovics M, Pindoria S, Cole TJ, Woolf AS. Primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. J Am Soc Nephrol. 2003;14:739-44. Garin EH, Olavarria F, Nieto VG, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics. 2006;117:626-32. Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics. 2008 [cited 2008 November 10];121:e1489-e1494. Available from: http://pediatrics.aappublications.org. Roussey-Kesler G, Gadjos V, Idres N, Horen B, Ichay L, Leclair MD, et al. Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol. 2008; 179:674-9. McLorie GA, McKenna PH, Jumper BM, Churchill BM, Gilmour RF, Khoury AE. High grade vesicoureteral reflux: analysis of observational therapy. J Urol. 1990; 144:537-40. Weiss R, Duckett J, Spitzer A. Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol. 1992;148:1667-73.
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93. Gil-Vernet JM. A new technique for surgical correction of vesicoureteral reflux. J Urol. 1984;131:456-8. 94. Chen HW, Lin GJ, Lai CH, Chu SH, Chuang CK. Minimally invasive extravesical ureteral reimplantation for vesicoureteral reflux. J Urol. 2002;167:1821-3. 95. Lakshmanan Y, Fung LC. Laparoscopic extravesicular ureteral reimplantation for vesicoureteral reflux: recent technical advances. J Endourol. 2000;14:589-93.
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96. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;175:716-22. 97. Sheu JC, Huang YH, Chang PY, Wang NL, Tsai TC, Huang FY. Results of surgery for vesicoureteral reflux in children: 6 years’ experience in an Asian country. Pediatr Surg Int. 1998;13:138-40.
rinary tract infection (UTI) is a leading cause of serious bacterial illness in febrile infants, afflicting at least 7% of those younger than 6 months of age and 5% of those 6 to 24 months of age.1 Throughout childhood the cumulative incidence is approximately 10% in girls and 3% in boys. Vesicoureteral reflux (VUR) is diagnosed most frequently after UTI, particularly in newborns and infants (36%-49% of cases), and in girls of all ages. At younger than 6 months of age no difference in the incidence between boys and girls is noted.2 Some cases of VUR are discovered because of antenatal hydronephrosis or through sibling screening. VUR is less common and less severe in African American children, compared with Caucasian children.3
U
*Department of Pediatrics, Division of Pediatric Nephrology, McGill University Health Centre, Montreal, Quebec, Canada. †Division of Pediatric Nephrology & Hypertension, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI. Dr. Mattoo is supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Address reprint requests to Tej K. Mattoo, MD, DCH, FRCP (UK), Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2009.03.011
Seminars in Nephrology, Vol 29, No 4, July 2009, pp 349-359
UTI
Pathogenesis Urinary infection usually is ascending, with inoculation of fecally derived organisms from the urethra and peri-urethral tissues into the bladder.4 The most prevalent pathogens in several recent pediatric studies were Escherichia coli (54%-67%), Klebsiella (6%-17%), Proteus (5%12%), Enterococcus (3%-9%) and Pseudomonas (2%-6%).5-7 Previously, E coli accounted for 80% to 90% of infections, and it is not clear if the change in frequency was caused by sampling bias (not all infections cultured) or a result of increasing antibiotic use. Among patients with urinary tract anomalies or impaired immune systems, less-virulent organisms, such as Staphylococcus epidermidis, Haemophilus influenzae, and group B Streptococcus, may be responsible. The hematogenous route of infection is far less common with generally different causal organisms, such as Staphylococcus aureus, Candida, and Salmonella; Pseudomonas aeruginosa and Proteus can infect by either route. Risk factors include obstruction and trauma. 349
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Bacterial Pathogenetic Factors The fimbriae of gram-negative bacteria adhere to urinary mucosal receptors, facilitating colonization and entry into host urothelial cells. Adherence also may impair the flushing action of urine flow.8 Fimbriae of uropathogenic E coli (UPEC) pilfer host iron, an essential metabolic factor, and secrete toxins. Cytotoxic necrotizing factor 1 and ␣-hemolysin, encoded by approximately 50% of UPEC, are associated with increased clinical severity.9 The toxins inflict extensive tissue damage, facilitate bacterial dissemination and release of host nutrients, and disable host immune effector cells.9 UPEC also can replicate within the urothelium, forming intracellular bacterial communities; these are protected from antibiotics and probably the host immune system, and may seed recurrent infection.10
Urothelium Defense Mechanisms and Inflammatory Response The normal bladder can clear itself of bacteria within 2 to 3 days through antibacterial properties of urine and its constituents, intrinsic mucosal defense mechanisms, and elimination by voiding.4 Locally produced urinary proteins may trap bacteria or interfere with their ability to adhere (eg, mucin and Tamm Horsfall protein, respectively).11 Clearing is impaired by inadequate micturition, frank residual urine, increased bladder pressure, bladder mucosa inflammation, or stones. Once attached, bacterial recognition by urothelial Toll-like receptors incites production of antimicrobial proteins (defensins), chemokines, and cytokines, including interleukin (IL)-1, tumor necrosis factor-␣, IL-6, and IL-8, leading to inflammatory cell recruitment. With microbial invasion of the kidney (pyelonephritis), acute and generally focal inflammatory cell infiltrates of the pelvic mucosa (pyelitis) and renal interstitium (nephritis) occur, accompanied by edema, tubular cell damage, and sometimes necrosis.4,12 Numerous elements may contribute to renal tissue damage, including specific bacterial virulence factors and the host inflammatory response.13 Genetic variability in infection response may influence disease severity and susceptibility to scarring.
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For example, IL-8 receptor (CXCR1) gene sequence variants and diminished expression recently were identified in UTI-prone children.14 It has been speculated that children with increased IL-8 responses have more pronounced symptoms of infection, leading to earlier diagnosis, improved bacterial clearance, and reduced risk of permanent cell damage.13 Renal injury after UTI results primarily from the host inflammatory response. Antibiotics significantly decrease urinary levels of IL-1, IL-6, and IL-8 as early as 12 to 24 hours after beginning treatment for febrile UTI, supporting the notion that early treatment (within 72 hours) is important to prevent renal scarring.13 CLINICAL PRESENTATION Young infants often present with fever alone (ⱖ38°C); irritability, vomiting, lethargy, or poor feeding variably may be present. For those younger than 3 months there is an increased risk of bacteremia and a greater possibility of undiagnosed congenital urologic malformations.15 Older children generally have more explicit symptoms of bladder inflammation and/or flank pain. A recent meta-analysis evaluated the diagnostic accuracy of UTI signs and symptoms in infants (3-24 mo) with fever (ⱖ38°C), and in verbal children (⬎24 mo) presenting with urinary or abdominal symptoms.16 For infants, any of the following increased the positive likelihood ratio (L) of UTI to 2 or more: history of prior UTI, fever of more than 24 hours’ duration or higher than 40°C, absence of circumcision in males, and suprapubic tenderness. Combinations of these findings amplified probability. For verbal children, the following symptoms were most reliable: abdominal pain with fever higher than 38°C (LR, 6.3; 95% confidence interval [CI], 2.5-16), back pain (LR, 3.6; 95% CI, 2.1-6.1), new-onset urinary incontinence (LR, 4.6; 95% CI, 2.8-7.6), dysuria (LR, 2.4; 95% CI, 1.8-3.1), and frequency (LR, 2.8; 95% CI, 2-4). Offensive urine odor was not predictive.16 DIAGNOSIS OF UTI
Specimen Collection A noncontaminated urine sample is fundamental. For infants and non–toilet-trained children,
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Table 1. Screening Urinalysis: Diagnostic Criteria for Urinary Tract Infection
True-Positive Rate (Sensitivity) Test and Positivity Criterion Dipstick Any nitrite only Any LE only Any nitrite or LE Both nitrite and LE Microscopy Gram stain any organisms Centrifuged urine ⱖ5 WBC/hpf Uncentrifuged urine ⱖ10 WBC/mm3 Enhanced U/A ⱖ10 WBC/mm3 plus GS⫹ Enhanced U/A ⱖ10 WBC/mm3 or GS⫹
No. of Summary Studies Estimate
False-Positive Rate (1-Specificity)
Range
Summary Estimate
Range
13 7 9 5
0.50 0.83 0.88 0.72
0.16-0.72 0.64-0.89 0.71-1.0 0.14-0.83
0.02 0.16 0.07 0.04
0-0.05 0.05-0.29 0.02-0.24 0-0.05
5 5 9 2 2
0.93 0.67 0.77 0.85 0.95
0.80-0.98 0.55-0.88 0.57-0.92 0.75-0.88 0.94-0.96
0.05 0.21 0.11 0.01 0.11
0-0.13 0.16-0.23 0.05-0.63 0.01 0.07-0.16
Abbreviations: GS, gram stain; hpf, high-power field; LE, leukocyte esterase; U/A, urinalysis; WBC, white blood cell. Adapted with permission from Pediatrics, Vol. 104, Page e54, Copyright © 1999 by the AAP.20
the most accurate method of collection is suprapubic bladder aspiration, however, it rarely is practical. Urethral catheterization or spontaneously voided clean midstream samples (usually obtained while disinfecting for catheterization or suprapubic bladder aspiration) are the most reliable alternatives. Perineal urine bag collection has a high rate of contamination and should be avoided for culture, but may help in screening infants older than 3 months for suprapubic bladder aspiration or urethral catheterization.17 For toilet-trained children, appropriate cleansing of the perineal/genital area before midstream urine collection is essential.18,19 This may be facilitated for girls by having them sit backward on the toilet seat.
Urinalysis Although urine culture is the gold standard for UTI diagnosis, more rapid screening may be required for preliminary clinical decision making. Urine Gram stain is the single most sensitive and specific test.20,21 Enhanced urinalysis (unspun urine hemocytometer white blood cell count and Gram stain) further improves sensitivity and specificity (Table 1).20,22 Microscopy of centrifuged urine for white blood cells per high-power field is inadequate. For older infants and children, urine dipstick testing for both
leukocyte esterase and nitrites may be used if microscopy is unavailable, however, urine still must be sent for culture and symptomatic children must be treated pending the results because the dipstick false-negative rate is significant (Table 1).20 Failure to diagnose and promptly treat a UTI because of a false-negative test is generally a greater risk than that of a brief provisional course of therapy for a false-positive result.
Urine Culture Bacterial colony count criteria to distinguish urine infection from contamination are operational, not absolute.23 Although 105 colony forming units (CFU) per mL (108 CFU/L) is the generally accepted diagnostic cut-off level for midstream urine samples, true infection with a lower colony count occurs (eg, reduced bladder incubation time owing to urinary frequency or high urine flow rate, presence of an antibacterial agent in the urine).23 Table 2 illustrates suggested CFU criteria for UTI diagnosis in children based on 8 publications.24 Some investigators recently proposed a threshold of greater than 5 ⫻ 104 CFU/mL for catheterized specimens,25 however, this view is far from universal; other investigators recommend a lower value, such as 104 CFU/mL, particularly in the
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Table 2. Urine Culture: Diagnostic Criteria for Urinary Tract Infection
Urine Collection Technique
CFU/mL (pure growth)
Probability of Infection
Suprapubic aspiration
Gram negative rod, any Gram positive cocci, more than a few thousand
⬎99% ⬎99%
Catheterization
⬎105 104-105 103-104
95% Likely Suspicious
Clean void (male)
⬎104
Likely
Clean void (female)
3 samples ⬎105 2 samples ⬎105 1 sample ⬎105 5 ⫻ 104-105 104-5 ⫻ 104
95% 90% 80% Suspicious Suspicious if symptomatic
Adapted from Hellerstein.24
presence of pyuria or symptoms suggestive of UTI.23,26 TREATMENT
Infants Younger Than 3 Months All febrile neonates should be treated with intravenous antibiotics pending urine, blood, and cerebrospinal fluid culture results. For infants older than 1 month but younger than 3 months of age with suspected or confirmed UTI, intravenous antibiotics are recommended after appropriate cultures (blood, urine, ⫾ cerebrospinal fluid). There have been no large prospective studies of outpatient management in this age group.27
Pyelonephritis: Infants Older Than 3 Months and Children A 2007 Cochrane Review concluded that 10 to 14 days of oral treatment with cefixime, ceftibuten, or amoxicillin/clavulanic acid was as effective as 2 to 4 days of intravenous therapy followed by oral, to complete 7 to 21 days of antibiotic treatment. Predominantly third- and fourth-generation cephalosporins were studied, therefore generalizability of results is limited. There were inadequate data to determine the optimal total duration. Single daily aminoglycoside dosing was as safe and effective as 8-hourly dosing.28 Because
antibiotic resistance patterns vary by geographic region and organism, awareness of local data is essential for initial empiric therapy. Final antibiotic choice should be based on culture and sensitivity results. Recently published pediatric data from North America and Europe show significant antimicrobial resistance rates for E coli: ampicillin (38%-65%), amoxicillin/clavulanic acid (7%-43%), and cotrimoxazole (8%-35%).5-7,29 Klebsiella and Proteus antibiotic resistance was similarly high, whereas their sensitivity to cefixime, ceftriaxone, and aminoglycosides generally was maintained. A recent study showed increased symptomatic relapse with ceftibuten compared with cotrimoxazole, possibly because -lactam antibiotics fail to eradicate uropathogens from the vaginal or intestinal microflora.30 Most studies of oral therapy excluded patients with major uropathology and were not stratified for the presence of dilating vesicoureteral reflux, so the results cannot be generalized to these children. Prompt antimicrobial therapy generally is believed necessary to diminish risk of renal scarring,31,32 however, 2 recent reports question this notion. A post hoc subgroup analysis of a pyelonephritis-oral antibiotic therapy study found no increase in scarring on dimercaptosuccinic acid (DMSA) scan for those treated late versus early.33,34 Patients excluded from their
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analysis were those who were most ill (severe clinical sepsis, dehydration, vomiting, or increased serum creatinine level).34 It is conceivable that the patients who presented later had less severe renal inflammation and were inherently at lower risk. Findings by Doganis et al35 were similar, but 50% of their study patients were lost to follow-up evaluation. Given the limitations of these studies, it seems prudent to err on the side of caution and not delay diagnostic evaluation or therapy.
Lower Urinary Tract Infection: Older Infants and Children A 2003 Cochrane Review found that most studies addressing short versus standard-duration oral antibiotic therapy for lower UTIs were of inferior quality.36 However, consensus opinions are that short-course (2-4 days) treatment for uncomplicated cystitis likely is effective.36,37 An adequately powered, well-designed, randomized, controlled trial is indicated. Short-course treatment recommendations are not for children with urinary tract pathology. UTI RECURRENCE Recurrent UTIs develop in approximately 75% of children whose first infection occurs before the age of 1 year, and in about 40% of girls and 30% of boys presenting after this age.37 Most studies of features predicting recurrence have important limitations.37 Risk factors identified include dilating VUR, family history of UTI, infrequent voiding, and inadequate fluid ingestion. Strategies that may help prevent recurrence include management of voiding dysfunction and increased fluid intake. The role of antibiotics is controversial and evidence weak; well-designed, randomized, controlled studies are lacking.38 LONG-TERM OUTCOME Approximately 70% of infants and children with their first febrile UTI have pyelonephritis39,40 and renal scars may follow in 15% to 30%.33,41 With timely appropriate therapy most infants and children recover promptly without major long-term sequelae, but a small number are at risk for significant morbidity, progressive renal damage, and renal insufficiency. Included are
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those with urologic abnormalities, dysplasia, and recurrent pyelonephritis.37 COVERT BACTIURIA Covert bactiuria (asymptomatic colonization of the urinary tract) is often an incidental finding during screening or follow-up evaluation after treatment of symptomatic UTI. If it is ascertained that the infant or child is truly symptom free, has a normal physical examination, normal voiding pattern, no impairment of renal function, and no anomalies on renal imaging, antibiotic therapy should be avoided.32 E coli strains causing asymptomatic bactiuria have evolved to persist for months to years in a commensal-like relationship with the host urinary tract and possibly protect it from colonization by more pathogenic UPEC.9 Elimination of these potentially protective bacteria may increase the risk of acute pyelonephritis. VUR AND REFLUX NEPHROPATHY VUR is a frequent pediatric urologic disorder affecting 1% to 2% of otherwise normal children.42 VUR is believed to predispose to UTI, and the two are linked with renal scarring. In 1960, Hodson and Edwards43 associated VUR with chronic pyelonephritis, which subsequently came to be known as reflux nephropathy.44 After acute pyelonephritis, renal scarring visible on intravenous urography takes about 1 to 2 years to develop, but is seen much earlier on DMSA.45,46 The International Reflux Study reported that renal injury is more frequent in children younger than 2 years old, particularly if VUR is high grade.47 Besides younger age, other factors that increase the probability of renal scarring in children with VUR and UTI include delayed treatment of UTI, recurrent UTI, higher grades of VUR, bacterial virulence, and possibly genetic factors such as angiotensin converting enzyme gene polymorphism.48-52 Renal scarring may occur in the absence of VUR and without UTI.53 In addition, the renal imaging abnormalities often referred to as renal scarring actually may represent congenital renal dysplasia in some patients. This is supported by renal imaging changes in infants and
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children with VUR but no history of UTI, as in infants with VUR diagnosed during postnatal follow-up evaluation for antenatal hydronephrosis and in siblings of index patients with VUR.54-56
Role of Voiding Dysfunction and Constipation VUR may be associated with voiding dysfunction or dysfunctional elimination syndrome, an abnormal pattern of elimination characterized by bowel and bladder incontinence and withholding, generally without underlying anatomic or neurologic abnormalities.57 Voiding dysfunction may predispose to recurrent UTI, induce and perpetuate VUR, adversely affect the results of ureteral reimplantation, and result in permanent renal damage.58-60 Constipation may increase the risk of recurrent UTI in children with VUR, as well as the likelihood of urinary incontinence, bladder overactivity, dyscoordinated voiding, and deterioration of VUR.61 Constipation causes compression of the bladder and bladder neck, resulting in increased bladder storage pressure and postvoid residual urine volume. The distended colon and/or soiling also provide a reservoir of pathogens.62-64
Complications of Reflux Nephropathy Reflux nephropathy has been reported to be responsible for 12% to 21% of all children with chronic renal failure.65,66 According to the North American Pediatric Renal Trials and Collaborative Studies 2006 Annual Report, 536 (8.4%) of the 6,405 children with chronic renal insufficiency had reflux nephropathy, which, according to the registry, is the fourth most common cause of chronic renal insufficiency after obstructive uropathy, renal aplasia/hypoplasia/dysplasia, and focal segmental glomerulosclerosis.67 However, in databases following up chronic kidney disease, dialysis, and transplant patients, labeling all those with renal imaging abnormalities and a past history of UTI or VUR as having chronic pyelonephritis or reflux nephropathy has lead to overestimation of the contribution of UTI and/or VUR to end-stage renal disease, and underestimation of the frequency of renal dysplasia.
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Hypertension has been reported to occur in 9% to 30% of children and young adults with renal scarring and it may take years to develop.68 It is believed to be caused by segmental ischemia with increased renin secretion and does not depend consistently on the severity of the scarring.68,69 In a study that involved blood pressure recording in 664 patients diagnosed with VUR between 1970 and 2004, there were 20 (3%) patients who developed hypertension.70 The estimated probability of hypertension was 2% at 10 years of age, 6% at 15 years of age, and 15% at 21 years of age. The survival analysis revealed that about 50% of children with unilateral and bilateral renal damage develop persistent hypertension at about 30 and 22 years of age, respectively. The presence of hypertension correlated strongly with the renal damage at entry.70 In a study on otherwise healthy children referred to a hypertension clinic, 33 (21%) of 159 patients were found to have renal scarring.71 The etiology of scarring in these patients was not studied and could have been caused by reasons other than UTI and/or VUR. Renal parenchymal injury may be associated with proteinuria, and in some cases nephrotic syndrome. Focal segmental glomerulosclerosis is known to occur in patients with reflux nephropathy.72 The suggested pathogenesis is glomerular hyperfiltration in remnant nephrons with modifications in permselectivity to macromolecules such as albumin and progression of renal disease.73,74 In a study in children having bilateral VUR with renal scarring and normal creatinine clearance, microalbuminuria was detected in 53.5% of the cases.74 Renal scarring also may cause pregnancy-related complications such as recurrent pyelonephritis, toxemia or pregnancy, low-birth-weight babies, and miscarriage.75-79 An increased risk of nephrolithiasis also has been reported in children with VUR.80
Management of VUR Primary VUR generally improves with time, particularly when the following factors are present: non-white race, lower reflux grade, absence of renal damage, and lack of voiding dysfunction.81 The traditional management has
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included prompt treatment of UTI and longterm antimicrobial prophylaxis until the resolution of VUR. Surgical intervention has been advocated in those with high-grade VUR, recurrent UTI despite antimicrobial prophylaxis, or noncompliance with medical management.
Antimicrobial prophylaxis A number of reports have raised serious doubts about the relevance of long-term antimicrobial prophylaxis for renal injury prevention in patients with VUR.82-84 Three systematic reviews have concluded the following: many published studies on antibiotic prophylaxis have been poorly designed with biases known to overestimate the true treatment effect.85 It is uncertain whether antibiotic prophylaxis or surgical treatment of primary VUR in children confers any clinically important benefit.86 VUR is a weak predictor of renal parenchymal damage in children hospitalized with febrile UTI.87 Some recent studies compared surveillance only with antibiotic prophylaxis in children with primary VUR, the end points for the studies being the frequency of UTI and/or renal scarring. No significant difference between the 2 groups was reported.88-90 The observations reported in these studies are important but are limited by a number of factors that include the number of patients studied, ages of the patients included in the study, lack of blindness, and urine collection methods in non–toilet-trained children.
Surgical intervention The decision for surgical intervention in VUR depends on multiple factors that include patient age, renal function, duration of follow-up period, and VUR grade. VUR grade V has the lowest rate of spontaneous resolution, particularly in older children, and some advise surgical intervention if there is no improvement within a year, particularly with recurrent infections on antimicrobial prophylaxis.84,91,92 Minimally invasive procedures include endoscopic injection of a bulking agent (Deflux; Q Med Scandinavia Inc., Princeton, NJ) at the ureterovesical junction, trigonoplasty,93 the use of small inguinal incisions for an extravesical surgical approach,94 or laparoscopic ureteral reimplantation.95 A meta-analysis of all of the endoscopic
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modalities used for management of VUR suggests rates of cure per ureter for grades I and II of 78.5%, grade III of 72%, grade IV of 63%, and grade V of 51%.96 The most commonly performed open technique (Cohen Cross trigonal reimplantation) remains the gold standard for the correction of VUR with a success rate of 97% to 99%.97 CONCLUSIONS The recent knowledge about UTI and VUR, and controversies regarding the extent of their role in renal scarring, has generated much interest among clinicians as well as researchers. The consequences of delayed versus early treatment of acute febrile UTI and the appropriateness of medical versus surgical versus no intervention for various grades of VUR will continue to be debated until more prospective, randomized, and preferably blinded and placebo-controlled studies are performed to confirm or refute these observations. One such study that started recruiting patients in 2007 is the Randomized Intervention for children with VesicoUreteral Reflux (RIVUR) study, which will evaluate the role of antimicrobial prophylaxis in children with grades I to IV VUR diagnosed after febrile UTI. In the meantime, it is advisable that VUR and UTI be considered risk factors for renal scarring and that each patient is treated with caution. REFERENCES 1. 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. 2. Chen JJ, Pugach J, West D, Naseer S, Steinhardt GF. Infant vesicoureteral reflux: a comparison between patients presenting with a prenatal diagnosis and those presenting with a urinary tract infection. Urology. 2003;61:442-6. 3. Chand DH, Rhoades T, Poe SA, Kraus S, Strife CF. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. J Urol. 2003;170:1548-50. 4. Tolkoff-Rubin NE, Cotran RS, Rubin RH. Urinary tract infection, pyelonephritis, and reflux nephropathy. In: Brenner BM, editor. Brenner & Rector’s the kidney. Philadelphia: Saunders Elsevier; 2007. p. 1203-38. 5. Gokce I, Alpay H, Biyikli N, Ozdemir N. Urinary tract pathogens and their antimicrobial resistance patterns in Turkish children. Pediatr Nephrol. 2006;21:1327-8.
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