|
Sunil Kumar Bhatnagar, MBBS, MD(Paed), MRCP, MRCPCH, Senior Paediatrician, Paediatric Infectious Diseases Unit, Child Health Department, The Royal Hospital, PO Box 1331, PC 111, CPO Seeb, Sultanate of Oman
Urinary tract infection (UTI) in infancy and early childhood is one of the commonest bacterial infections, and is important because of the acute morbidity and the potential for long-term medical problems related to reflux nephropathy (renal scarring), such as hypertension and renal insufficiency. It is difficult to differentiate between upper UTI (pyelitis/pyelonephritis) and lower UTI (cystitis/urethritis) in infants and young children because the signs and symptoms are often non-specific, with fever as the most common initial complaint. Since young children with a febrile UTI may have acute pyelonephritis with renal scarring, imaging studies and careful follow-up are crucial to management; renal damage may be minimised or avoided by appropriate therapy. Renal scarring following UTI, best detected by dimercaptosuccinic acid renal scintigraphy, may occur both in the presence and in the absence of vesicoureteric reflux (VUR). Because VUR is an inherited condition, radiological evaluation should be considered for asymptomatic siblings of children who have UTI and VUR.
INTRODUCTION
Urinary tract infections (UTIs) are one of the most common bacterial infections in children, occurring in 3-5% of girls and 1-2% of boys. UTIs are important because they cause acute morbidity and may result in long-term medical problems, including hypertension and reduced renal function. Management of children with UTI involves repeated patient visits, use of antimicrobials, exposure to radiation, and cost. Accurate diagnosis is extremely important for two reasons: to permit identification, treatment and evaluation of the children who are at risk for renal damage, and to avoid unnecessary treatment and evaluation of children who are not at risk, for whom interventions are potentially harmful and provide no benefit.1 Good follow-up care is the hallmark of adequate management of young children with UTI.
The incidence of first-time UTI is highest during the first year of life. Before 1 year of age, girls have a lower risk of UTI than boys, particularly uncircumcised boys who have a >10-fold higher incidence of infection than girls or circumcised boys.2 Recognition of a young child at risk for UTI is important from the management point of view; factors increasing the risk of UTI in children are shown in Table 1. In girls the recurrence rate for UTI is substantial, regardless of the presence or absence of a urinary tract abnormality. The greatest risk of recurrence is during the first few months after an infection.3 Data support the concept that delay in instituting appropriate treatment of acute pyelonephritis increases the risk of renal damage; the risk of renal damage increases as the number of recurrences increases.4
In children outside the neonatal period and without complicating disorder of the urinary tract (such as calculus, obstruction or neurogenic bladder), the vast majority of UTIs (>80%) are caused by Escherichia coli. Other organisms associated with UTI in children include Klebsiella, Proteus, Enterobacter, Pseudomonas, Enterococcus (during the first 3 months of life most commonly), Staphylococcus aureus (mostly associated with indwelling catheters), group B Streptococcus (neonatal pathogen), Adenovirus (haemorrhagic cystitis) and Candida spp. (mostly a neonatal pathogen). A recently published study of children admitted to a tertiary care hospital with the diagnosis of community-acquired UTI indicates that the prevalence of non-E. coli uropathogens is increasing, particularly in high-risk groups (including boys, children with genitourinary abnormalities and cases with previous antibiotic usage).5
There are three basic forms of UTI: upper UTI (pyelonephritis/ pyelitis), lower UTI (cystitis/urethritis) and asymptomatic bacteriuria. It is difficult to differentiate between upper and lower UTI in infants and young children because the signs and symptoms are often non-specific, with fever as the most common initial complaint. As many as 25% of children without symptoms of pyelonephritis are found by ureteral catheterisation to have renal bacteriuria.6
Clinical manifestations of upper UTI include any or all of the following: abdominal or flank pain, fever, malaise, nausea, vomiting and occasionally diarrhoea. Newborns and infants may show non-specific symptoms such as jaundice, weight loss, poor feeding, vomiting and irritability. UTI is an important and common cause of fever of uncertain aetiology in infants and young children. Involvement of the renal parenchyma is termed acute pyelonephritis whereas, if there is no parenchymal involvement, the condition may be termed pyelitis. Acute pyelonephritis may result in renal injury, which is termed pyelonephritic scarring. Children of any age with a febrile UTI may have acute pyelonephritis with renal scarring. The exception to this is the child with UTI and a normal dimercaptosuccinic acid (DMSA) scan by 4 years of age, when the risk of pyelonephritic scarring from future UTIs is probably low.7
Symptoms of cystitis include dysuria, urgency, frequency, suprapubic pain, incontinence and malodorous urine. Fever is generally not more than 38.5ºC. Cystitis does not result in renal injury.
The ability to empty the bladder completely and regularly is the most important host defence against UTI. Infected bladder urine can remain confined or can ascend to the upper urinary tract. Vesicoureteic reflux (VUR), an important risk factor for the development of pyelonephritis, is found in 30-50% of children with UTI.6 A population-based cohort study of 1221 children, followed prospectively after their first UTI, found boys with primary congenital VUR-associated renal scarring and girls with acquired scarring related to recurrent febrile UTIs.8
CLINICAL APPROACH
History
In addition to the identification of symptoms consistent with UTI, the history should be reviewed for previous UTI, undiagnosed febrile episodes, urethral or vaginal discharge, sexual abuse, trauma, constipation, pinworms, infrequent voiding, tight clothing, bubble baths and family history of VUR or recurrent UTI.
Physical examination
This should include evaluation of growth curve, vital signs (particularly blood pressure), abdominal examination for flank masses, flank or suprapubic tenderness, bowel distension, faecal impaction; meatal stenosis and/or circumcision in boys, vulvovaginitis or labial adhesions in girls, neurological examination of lower extremities, perineal sensation and reflexes, and rectal and/or sacral examination.
Urine collection
Performance of a quantitative urine culture is necessary for confirmation of UTI. Bag specimen collection is not appropriate for the diagnosis of UTI at any age, because of the substantial rate of contamination. Suprapubic aspiration (SPA) is the most reliable technique for obtaining a urine specimen for culture (Table 2). Urethral catheterisation also provides a reliable specimen. These two methods of urine collection have low contamination rates, thus avoiding the risk of overdiagnosis, overtreatment and unnecessary evaluation associated with bag collection. Timing of specimen collection is important; sensitivity is greatest with first voided morning specimens, because the pathogens have had the opportunity to incubate overnight in the bladder.
Laboratory diagnostic criteria
Presumed UTI is diagnosed while urine culture results are pending in a child with an abnormal urinalysis and clinical findings consistent with UTI. Abnormal urinalysis (Table 3) is defined as a positive result for any of the following studies: nitrite test, leukocyte esterase, microscopic examination and Gram stain of unspun urine. A Gram stain showing one bacterium/high power field (hpf) in uncentrifuged urine represents at least 105 colonies/ml. Definite UTI is defined by a positive urine culture in a child presenting with a clinical profile consistent with UTI. A positive urine culture is defined as a single organism cultured from an SPA, catheter specimen or a clean-catch specimen (Table 4). No absolute cut off for the number of bacterial colonies/ml can perfectly predict the presence or absence of a UTI.
MANAGEMENT
Management of UTI consists of antibiotic therapy for the acute episode, prevention of further episodes, imaging studies and careful follow-up. Figure 1 depicts the diagnostic decision tree for UTI in young children.
Treatment of acute UTI
Admission to hospital is indicated if the child is aged <3 months, is toxic or appears ill, if significant genitourinary abnormality is suspected, if the child’s condition precludes the use of oral therapy, or if there is uncertainty about outpatient care.
Inpatient management of UTI includes administration of parenteral fluids and intravenous antibiotics. The initial choice of antibiotic before the results of the culture and sensitivities are known depends on the age of the child and the degree of illness (Table 5). The intravenous route for therapy is usually continued for 48 hours (with the exception of neonates, who generally require 10-14 days of intravenous therapy) if the child is clinically improved and afebrile. Treatment with an oral antibiotic to which the infecting organism is susceptible is substituted when fever subsides, the total duration of therapy being 10-14 days. After the treatment is completed patients should receive prophylactic doses of antibacterial medication, most commonly nitrofurantoin or trimethoprim-sulfamethoxazole (TMP-SMX), daily at bedtime, at least until radiological evaluation is completed and assessed.1 The doses of nitrofurantoin and TMP-SMX for urinary prophylaxis are 1-2 mg/kg and 2-4 mg/kg of TMP component, respectively, daily at bedtime as single dose.
Children with bacterial cystitis can be treated with an oral antibiotic; a course of 7 days is adequate in most instances.
Prevention of further episodes of UTI
The following precautions may be taken to prevent further UTI episodes: Avoid constipation. Wiping should be done in a front-to-back direction for girls. Avoid irritating soaps and bubble baths. Encourage the child to sit on the toilet regularly and to empty the bladder. Encourage the child to drink fluids as much as possible during the day and to empty the bladder properly last thing at night. Avoid tight underpants or pantyhose. To prevent episodes of UTI, observe the medical indications for circumcision for boys, which include: prenatal hydronephrosis in newborns who are found to have VUR in the neonatal period, high-grade VUR and VUR associated with unilateral renal agenesis or multicystic kidney.
The following guidelines for bladder catheter care reduce the risk of UTI in catheterised patients: Use catheters only when absolutely necessary; remove as soon as possible. Catheters should be inserted aseptically and maintained by trained personnel only. A sterile closed drainage system is mandatory. The catheter and drainage tube must never be disconnected except when irrigation is necessary to relieve obstruction. Strict aseptic technique is employed under these circumstances. Obtain urine for culture by aspirating the catheter with a 21-gauge needle after the catheter is prepared with povidone-iodine. Maintain downhill, non-obstructed flow, with the collection bag always below the level of the bladder and emptied at frequent intervals. Replace indwelling catheters when obstruction or concretions are demonstrated. Strict handwashing precautions should be observed by staff caring for these patients. Administer prophylactic antibiotics during catheter insertion and removal to patients with cardiac disease (particularly prosthetic valves) that predisposes to bacterial endocarditis.
Imaging studies
Diagnostic imaging is critical to the evaluation of young children with a febrile UTI.9 Imaging studies are indicated after a first documented UTI in any boy or girl younger than 6 years of age. The important reason for investigating children with a UTI is to detect or exclude any renal or urinary tract abnormality that may be correctable or may predispose to repeated infections and long-term renal damage. The commonest abnormality detected is VUR. The imaging studies include ultrasonography, cystography (micturating cystourethrogram or radionuclide cystography) and renal cortical scintigraphy using technetium 99-labelled DMSA). Table 6 summarises the roles of major categories of radiological investigations in young children after their first UTI. At the present time there is no clear international consensus on the imaging protocol to be followed after a first childhood UTI; Figure 2 shows an algorithmic approach to imaging studies in a child with UTI.
DMSA scintigraphy can visualise acute inflammation in addition to permanent uptake defect; the acute inflammatory changes may be transient and may disappear within 6 months of acute infection. Reflux nephropathy is focal or generalised damage of a kidney, and there is an association of reflux nephropathy with past or present VUR. The process of scarring after acute pyelonephritis is slow, occurring more often after repeated infections (Figure 3). Children with unilateral damage, which is most common, develop compensatory hypertrophy of the other kidney and the total glomerular filtration rate (GFR) remains within the normal range. In children with bilateral damage, the GFR often is decreased. However, during the last decades the more aggressive diagnostic and therapeutic approaches used in infancy and early childhood seem to have decreased the risk of UTI leading to chronic renal failure.
A number of risk factors are associated with permanent pyelonephritic renal damage (Table 7). Although VUR is a major risk factor for the development of renal scarring, many children are found to have a scarred kidney but no evidence of VUR.10 Probably the child has grown out of VUR by the time scarring is detected. However, in children older than 3 years at the time of their original DMSA, very few first scars were reported and none in those who were older than 4 years.7
There is no ideal test for the detection of VUR. The contrast micturating cystourethrogram (MCUG) is often quoted as the gold standard, but it has limitations. It is not physiological, because of the presence of a catheter, and it only shows whether VUR exists over a very short period of time, whereas VUR may be intermittent and of fluctuating nature. Radionuclide cystography may detect intermittent VUR, as prolonged imaging can be performed.
Because of the association between recurrent UTI (the risk of recurrence is highest in the first 6 months following the UTI episode) and scarring, after the acute course of antibiotics, low-dose prophylactic antibiotic therapy with a suitable agent (TMP-SMX or nitrofurantoin most commonly) should be continued until at least the imaging investigations are completed and assessed.1
Prophylactic antibiotic therapy
After an episode of acute pyelonephritis, infants and young children (with or without VUR) are at risk for recurrence of infection, particularly during the ensuing 6 months. For the following groups of patients, who are at high risk for developing renal scarring, low-dose antibiotic prophylaxis is indicated: Children with VUR of any grade until surgical or spontaneous resolution. Children with frequent recurrences of lower UTI (>3 times/year), particularly when associated with underlying bladder atony or abnormal voiding patterns. In conjunction with prophylactic therapy, voiding disorder or constipation should be corrected. Neonates diagnosed with hydronephrosis antenatally until appropriately evaluated. Children with documented UTI awaiting radiological evaluation. Possibly children <3 years age for at least 6 months (or until the child has reached 3 years of age) after an acute episode of pyelonephritis; the rationale is that it is difficult to make a prompt diagnosis of recurrent UTI in children <3 years of age. Possibly neonates and infants <1 year of age, who present with febrile UTI and/or DMSA changes, assuming there is no VUR. Cases in which a new scar appears on DMSA scans.
Compliance is crucial to prophylaxis. The patient and the family must be motivated. During prophylaxis, recurrences caused by bacteria sensitive to the prophylactic drug usually indicate non-compliance. The drugs most commonly used for prophylaxis are nitrofurantoin, trimethoprim (TMP) and TMP-SMX. Amoxicillin may be substituted during the first 2 months of life. Nitrofurantoin is the drug of choice for prophylaxis, because it attains high concentration in the urinary tract, it has little effect on normal gut flora and resistance is rare. TMP-SMX is the drug of second choice; it also eliminates periurethral enterobacterial colonisation, besides having an antibacterial action on the urine. The side effects of TMP-SMX are mostly due to the sulfonamide component; in such cases, TMP may be used instead.
Management of VUR
VUR is the retrograde flow of urine from the bladder into the ureters and renal pelvis. Reflux is an autosomal-dominant inherited trait with variable penetrance, is usually congenital, occurs in families and affects approximately 1% of children in the general population. Reflux is much more common among white than black children. The incidence of VUR in girls evaluated after their first UTI is between 25% and 40%. Reflux predisposes to pyelonephritis,11 which may result in renal injury or scarring (reflux nephropathy). Reflux is unlikely to cause renal injury in the absence of infection. Extensive renal scarring impairs renal function and may result in renin-mediated hypertension, renal insufficiency or end-stage renal disease, impaired somatic growth, and morbidity during pregnancy. Reflux severity is graded using the International Study Classification of I to V,12 and is based on the appearance of the urinary tract on a contrast MCUG (Figure 4). The higher the reflux grade, the greater is the likelihood of renal injury. About 35% of siblings of children with reflux also have reflux, the majority being asymptomatic. The likelihood of a sibling having reflux is independent of the grade of reflux or the gender of the index child. Approximately 12% of asymptomatic siblings with reflux have evidence of renal scarring.
The natural history of VUR is for spontaneous resolution or improvement to occur over time. The mean age at reflux resolution is 6-7 years. Lower grades of reflux are much more likely to resolve than are higher grades; Grade V reflux rarely resolves.
The treatment of VUR is either medical or surgical (Table 8). The goals of treatment are to prevent pyelonephritis, renal injury and other complications of reflux. The choice of treatment (antibiotic prophylaxis versus surgery) remains a value judgment governed by such local factors as preference of the parents, availability of skilled surgeons, availability of closely supervised medical treatment and willingness to comply with prolonged periods of prophylaxis.
Continuous antibiotic prophylaxis is the cornerstone of the initial management of children with VUR. The duration of antibiotic prophylaxis is controversial. Prophylaxis is usually continued until reflux resolves or until the risk of reflux to the child is considered to be low. A cystogram (MCUG or RNC) is generally performed every 12-18 months. Greenfield et al.13 suggest that prophylactic antibiotics should continue until reflux resolves, no matter what the age, and two normal voiding cystourethrograms (VCUGs), 12 months apart, have been obtained. It was observed that 27% of children will demonstrate VUR again after a single normal VCUG study. In contrast, Belman14 and Winberg15 suggest that prophylaxis should be discontinued in children older than 7 years, even if low-grade VUR persists. During the period of antibiotic prophylaxis, culture of the urine is indicated only if the child is symptomatic; breakthrough UTI should be treated as acute UTI. An MCUG should not be repeated without good reason, as a great deal of VUR resolves with time, and the damage is done early.
The duration of antibiotic prophylaxis also depends on whether or not scarring is demonstrated on DMSA scintigraphy, which remains the gold standard for the detection of renal scarring. At the end of a 2-year period of prophylaxis, repeat the ultrasound study and DMSA scintigraphy. Prophylaxis is discontinued after the 2-year period if the following conditions are fulfilled: The child has been free of infection. There are no scars on DMSA or ultrasound. The child may be discharged to primary care and monitored for repeat infection. There is annual review of scarring in one kidney. Reinstate prophylaxis after a further documented UTI, repeat ultrasound and DMSA in a further 2 years, and carry out annual blood pressure monitoring. There is bilateral renal scarring, when children are at greater risk of long-term complications of renal insufficiency and/or hypertension. The management guidelines for these children include referral to specialist paediatric nephrology and urology, lifelong blood pressure monitoring, and MAG3 scanning with indirect cystography combined with GFR measurement studies using 51Cr ethylene diamine tetra-acetic acid at 5-year follow-up.
Because VUR is an inherited condition, radiological evaluation should be considered for asymptomatic siblings of children who have UTI and VUR.
Management of a child found to have renal scar
Management of a child with a renal scar should take the following course: Establish whether there is VUR. Initiate antibiotic prophylaxis to prevent the extension of the scar while VUR persists. Initiate lifelong blood pressure monitoring. Consider surgical treatment of reflux in cases of failed medical treatment, breakthrough infection or non-compliance. Discuss with the family the familial nature of VUR and increased risk in siblings.
Indications for referral to a paediatric urologist after UTI include: Dilating VUR. Marked bilateral renal scarring on DMSA scintigraphy at >4 months after UTI. Obstructive lesions (e.g. pelviureteric junction obstruction, ureterocele, ureteral diverticulum, megaureter, posterior urethral valves, neurogenic or markedly trabeculated bladder). Non-compliance with antibiotic therapy. Failure of kidney growth on yearly sonograms. Elevated serum creatinine concentration. Hypertension.
CONCLUSIONS UTIs in infancy and early childhood are important because of the acute morbidity and the potential for long-term medical problems related to reflux nephropathy (renal scarring) such as hypertension and renal insufficiency. Accurate diagnosis of UTI in young children is extremely important to permit identification, treatment and evaluation of those at risk for renal damage and to avoid unnecessary treatment and evaluation of those children who are not at risk, for whom interventions are potentially harmful, and provide no benefit. Differentiation between upper UTI (pyelitis/pyelonephritis) and lower UTI (cystitis/urethritis) in infants and young children is not easy because the signs and symptoms are often non-specific, with fever as the most common initial complaint. Imaging studies and careful follow-up are crucial to the management of young children with acute febrile UTI. VUR is an inherited condition; radiological evaluation should be considered for asymptomatic siblings of children who have UTI and VUR. When indicated, timely referral to pediatric nephro-urology services is useful to reduce the long-term morbidity associated with pyelonephritic renal scarring.
|
