Urinary Tract Infections
Gangadarshni Chandramohan, MD, MSc, FASN, FAAP
A 2-year-old girl is brought to the office with a 1-day history of fever (temperature of 39.4°C [103°F]), vomiting, and mild diarrhea. No history exists of any change in her urinary habits, and she still wears diapers. The child has been somewhat irritable but fully alert.
Physical examination reveals an ill-appearing toddler. Her temperature is 39.2°C (102.6°F), heart rate is 122 beats per minute, respiratory rate is 30 breaths per minute, and blood pressure is 90/60 mm Hg. The neck is supple. Head, eye, ear, nose, throat, chest, heart, abdomen, and genital examinations are normal. Urinalysis shows specific gravity of 1.025, pH 6.0, leukocyte esterase and nitrite both strongly positive, protein trace, and blood trace; the sediment has 15 to 20 white blood cells and 2 to 4 red blood cells per high-power field. The Gram stain shows more than 100,000 gram-negative rods, and the urine culture result is pending.
1. What are the possible diagnoses for the child with positive leukocyte esterase on urinalysis?
2. What are the indications for hospital admission for the child with a urinary tract infection?
3. What antibiotics are used in the management of urinary tract infection?
4. What is the appropriate diagnostic workup for the child with suspected urinary tract infection?
5. When should renal ultrasonography and voiding cystourethrography be done in the child with a urinary tract infection?
6. If the workup is positive for vesicoureteral reflux, how should the child be treated in the long term?
Urinary tract infection (UTI) is among the most common bacterial infections affecting infants and children. Children with UTI frequently present with urinary symptoms such as dysuria, frequency, and urgency. Young infants and toddlers may present with nonspecific symptoms, as with other types of bacterial infection. Further, because of the subtle nature of the symptoms at the early stages of disease, medical intervention may be delayed, resulting in overwhelming sepsis. In most children, UTIs resolve completely with appropriate antibiotic therapy. In the child with an underlying anatomic or functional abnormality of the genitourinary system, such as vesicoureteral reflux (VUR) or bowel-bladder elimination dysfunction, respectively, or with delayed or inadequate antibiotic treatment, however, UTI may result in renal scarring that can sometimes cause hypertension or, rarely, end-stage renal disease.
Urinary tract infection is a nonspecific, generic term implying significant bacteriuria, irrespective of the site of bacterial growth in the urinary tract. In many young children with bacteriuria, clinical findings overlap, and precise classification is not easily made. Some commonly used terms are clarified as follows.
Asymptomatic, covert, and screening bacteriuria are synonymous terms usually used when bacteriuria is detected during surveys of healthy children. The pediatrician should be aware, however, that some affected children, particularly those who are at high risk for developing UTIs, may have subtle urinary symptoms on close questioning. Those children should be treated for UTI using the same principles as used for children who present with obvious symptoms.
Cystitis implies infection of the bladder only. Main features of cystitis are voiding symptoms, such as dysuria, frequency, urgency, enuresis, and foul-smelling urine. Fever, if present, is usually low grade, and the patient may present with lower abdominal pain as well.
Acute pyelonephritis is infection of renal parenchyma characterized by systemic symptoms, such as high fever, chills, flank pain, and vomiting along with voiding symptoms.
Chronic pyelonephritis is a term that has been used in various ways. Ideally, it should be used only to refer to renal scarring resulting from repeated infections as diagnosed based on histologic analysis of renal biopsy specimens. Practically, the term often refers to scarred kidneys as demonstrated by nuclear medicine studies or reduced kidney function.
Urethritis implies infection of the urethra and usually occurs in the setting of sexually transmitted infections. The usual symptoms are dysuria and urethral discharge.
Bacteriuria is detected in approximately 1% of girls and 2% of boys during routine screening of healthy newborns and young infants in the United States. Approximately 1% of girls continue to have asymptomatic bacteriuria throughout childhood. Bacteriuria in boys older than 1 year is very uncommon. In most affected infants and children, bacteriuria resolves spontaneously with time and does not cause renal damage.
Symptomatic UTI occurs in approximately 2.5% of children annually and accounts for more than 1 million office visits per year. Up to approximately 7% of girls and 2% of boys have culture-proven symptomatic UTI by age 6 years. Before the age of 1 year, UTI recurs in 75% of infants. After 1 year of age, 40% of girls and 30% of boys develop recurrent UTIs following the first episode. In early infancy, UTI is approximately twice as common in boys as in girls and approximately 10 times more common in uncircumcised boys than circumcised boys. After the first 6 months of age, the prevalence of symptomatic UTI becomes considerably higher in females than males, and the difference between circumcised and uncircumcised males disappears. Among vaccinated febrile infants, UTI is the source of fever in approximately 4% to 8% of patients, even in those with symptoms of upper respiratory infection.
Signs and symptoms of UTI in neonates and young infants are usually nonspecific and include fever, irritability, poor weight gain (or weight loss), diarrhea, vomiting, and jaundice. Occasionally, bacteremia or sepsis with temperature instability, cyanosis, and disseminated intravascular coagulation may occur. Older children often have similar signs and symptoms, and often they are able to describe abdominal or flank pain, dysuria, frequency, urgency, enuresis, foul-smelling or cloudy urine, and occasionally gross hematuria (Box 112.1).
The pathogenesis of UTI involves interaction between various bacterial factors and protective host factors.
Escherichia coli accounts for 80% to 90% of first infections. The remainder are caused by other gram-negative enteric bacilli (eg, Proteus, Klebsiella, Enterobacter) and gram-positive cocci (eg, enterococci, Staphylococcus saprophyticus). Rarely, Morganella morganii, Proteus mirabilis, Providencia stuartii, and Serratia species can cause infection in young children as well. Most organisms that cause UTI originate from the fecal flora. Infections caused by S saprophyticus, a coagulase-negative staphylococcus, occur mostly in adolescents with UTI. Nosocomial infection can be caused by Citrobacter, Enterobacter, Enterococcus, and Pseudomonas.
Box 112.1. Clinical Features of Urinary Tract Infection
•Burning or pain on urination
•Leukocyturia or positive nitrite on urinalysis
•Positive urine culture
Microorganisms that cause UTI usually enter the urinary tract by an ascending route. To initiate colonization and infect the urinary tract, these organisms must first adhere to uroepithelium to avoid being swept away during voiding. Bacterial adhesion in E coli is mediated by fimbriae, which are fine, hair-like proteins emanating from the bacterial cell wall. One important type of fimbriae, P fimbriae, adheres to receptors on the uroepithelium, and some studies have shown that women and children with recurrent UTI have increased numbers of these receptors. In most young children with normal anatomy, acute pyelonephritis is caused by E coli with P fimbriae. In most patients with VUR and scarred kidneys, however, the infection is caused by E coli without P fimbriae. Thus, the role of P fimbriae in the pathogenesis of renal scarring is uncertain. Additionally, many of these bacteria, which are typically extracellular organisms, can survive and flourish intracellularly by taking advantage of the nutrients of the host cell and evading immune defenses. Other bacterial virulence factors include K and H antigens, colicin, and hemolysin; however, their role in the pathogenesis of UTI is not clearly defined.
Many unalterable host factors contribute to the pathogenesis of UTI, including age, sex, genetics, anatomy, and immune response to infection. Females seem to be at increased risk for UTI because the female urethra is shorter than the male urethra and closer to the anus. As previously stated, the uroepithelium of older girls and adult women who develop recurrent UTI binds E coli more avidly than uroepithelium from nonsusceptible individuals. Additionally, individuals with certain P and Lewis blood groups develop more UTIs than others without these specific blood groups. Urinary obstruction or other anomalies may contribute to the development of UTIs in approximately 2% of girls and 5% of boys, especially infants.
Vesicoureteral reflux is the retrograde passage of urine from the bladder to the ureter. After passage through the bladder wall, the normal ureter tunnels under the bladder mucosa for approximately 2 cm before it opens into the bladder lumen. Under normal circumstances, the submucosal segment is compressed when the bladder is filled and during voiding, thus preventing urine backing up into the ureter. Most VUR is primary and caused by a congenital abnormality of the ureterovesical junction, with the ureter having a short submucosal segment and more laterally placed openings. Reflux also may occur in the presence of normal ureteral anatomy when bladder pressures exceed 40 cm of water, as seen in patients with posterior urethral valves or neurogenic bladders resulting from inadequate emptying of bladder creating high pressure inside the bladder and causing leakage of urine back into the ureter. Vesicoureteral reflux is graded on a scale of 1 through 5, with stage 5 being the most severe based on radiologic imaging (Figure 112.1). However, nuclear voiding cystourethrography (VCUG), an alternative study that involves reduced radiation exposure but poor resolution, has been recommended for screening in girls. Because of the poor resolution, however, staging is less precise than with radiologic grading of VUR. Therefore, nuclear VCUG grading has only 3 stages: mild, moderate, and severe.
Figure 112.1. Grading of vesicoureteral reflux by vesicoureterography based on international classification. 1, Ureter only. 2, Ureter, pelvis, and calyces, but without dilatation. 3, Mild or moderate dilatation of ureter and mild or moderate dilatation of renal pelvis, but no or slight blunting of fornices. 4, Moderate dilatation or tortuosity of the ureter with moderate dilatation of renal pelvis and calyces and complete obliteration of the sharp angles of fornices, but maintenance of papillary impressions in most calyces. 5, Gross dilatation and tortuosity of ureters, renal pelvis, and calyces; papillary impressions are no longer visible in most calyces.
The incidence of VUR in normal infants is generally stated to be less than 2%; however, recent studies suggest that the incidence of low-grade VUR is much higher, particularly in preterm infants, than previously thought and may be similar to that in older children with UTI. In infants with UTI, the prevalence of VUR is approximately 25% to 50%; in school-age children, approximately 25% to 30%; and in adolescents, approximately 10% to 15%. These findings suggest that VUR often spontaneously resolves with increasing age and maturation of the bladder wall. Vesicoureteral reflux may be a familial disorder and has been reported in 10% to 30% of siblings of index cases. The incidence of UTI is increased in the presence of VUR, likely because of bladder and bowel dysfunction (BBD) or bladder elimination dysfunction resulting in a high amount of residual urine, which refluxes into the ureters or kidneys. This also provides infected urine direct access to the kidneys, which can result in pyelonephritis and, potentially, renal scarring.
It would seem that the greater the severity of VUR in the child with UTI, the greater the likelihood of renal scarring. Recently, however, it has been clearly recognized that many neonates (especially boys) with antenatal VUR, even in the absence of UTI, have congenital dysplastic renal parenchymal defects that had been misidentified as infective scars. Therefore, it is now presumed that the progression of renal scarring in such patients occurs as a result of the natural course of the congenital defect, with or without UTI.
Although many predisposing host factors cannot be changed, several potentially modifiable behaviors related to elimination are associated with UTI in older children. The school-age child with frequent reports of dysuria or recurrent UTIs with no history of UTI as an infant should be questioned for symptoms of dysfunctional voiding, a term often applied in the setting of children (especially girls) with no neurologic or anatomic abnormalities but who exhibit abnormal voiding behavior. Such girls often hold their urine for so long that they need to rush to the bathroom, only to incompletely empty their bladder, resulting in urinary stasis and the potential for infection. Additionally, the constipation and abnormal stooling patterns that frequently are associated with dysfunctional voiding are characteristic of BBD. In children between the ages of 6 and 12 years, recent data reveal BBD resulting in diurnal urinary incontinence in 30.7%, holding maneuvers in 19.1%, and urinary urgency in 13.7%, all of which can predispose to UTI.
In infants and young children, symptoms of UTI are often nonspecific. Thus, a high degree of suspicion for UTI must be maintained. An acute abdomen may rarely be confused with UTI. Some children with dysuria may have chemical irritation from exposure to materials such as bubble baths. A girl with overweight may retain urine in the labial folds, which can cause maceration, urethral irritation, vulvitis, and/or nonspecific vaginitis. Similarly, some young girls do not sit with their legs spread wide enough on the toilet, which can result in reflux into the vagina and cause post-void dribbling with subsequent urethral irritation or vulvitis and/or nonspecific vaginitis. In these patients, urinalysis may be positive for blood or sometimes leukocytes; however, urine culture findings usually help differentiate UTI from perineal flora contamination or vulvitis and/or nonspecific vaginitis or urethral irritation.
In all infants and young children with fever without an apparent source, urinalysis, urine Gram stain, and urine culture should be obtained to evaluate for UTI before initiating antibiotic treatment. If the febrile child younger than 2 years does not appear to be ill, workup should be based on risk assessment. In the older child, a history of fever, dysuria, frequency, abdominal pain, and nausea and vomiting is suggestive of UTI (Box 112.2). The physician should also inquire about any history of previous UTI, abnormal voiding, and constipation.
Bladder and bowel dysfunction is a common risk factor for constipation, urinary incontinence, or enuresis, which can predispose to UTI among school-age children. Lower urinary tract symptoms must be investigated carefully at routine pediatric visits.
Recurrent UTI generally refers to reinfection with a new organism, whether the same or a different species. This is a common problem, especially in the first year after initial UTI. Reinfection with the same organism is infrequent; however, if intermittent symptoms of UTI persist during administration of antibiotics and repeat urine culture is positive after 14 days, the initial infection is characterized as persistent. Persistence is the result of medication noncompliance or inappropriate choice of antibiotic (ie, the pediatrician has not followed up on the sensitivity results and changed the antibiotic accordingly). If symptoms relapse within 2 months even after a negative culture was obtained at 14 days after completion of antibiotic treatment, the condition is characterized as a relapse of the previous infection; that is, the infection remained latent and flared after completion of antibiotic treatment. Relapse may be indicative of underlying structural or functional problems of the urinary tract, kidney stones/hypercalciuria, or often, inappropriate antibiotic therapy. If an underlying structural or functional problem is suspected by the pediatrician, appropriate workup should be initiated, and nephrology or urology referral should be made based on those results.
Weight and height measurements are important to determine whether a patient has a chronic renal condition that may be predisposing to infections, such as obstructive uropathy or neurogenic or nonneurogenic bladder with secondary or primary VUR. The physician should check all vital signs to help determine whether the UTI involves the lower or upper tracts and to assess the severity of infection. An elevated blood pressure and temperature are consistent with an upper tract infection. The abdomen should be examined for masses and tenderness, the genitalia for local lesions, and the lumbosacral area for anomalies (eg, deep sacral dimples, tuft of hair, lipoma, hyperpigmentation, hemangiomas).
Box 112.2. What to Ask
Urinary Tract Infection
Children Age 2–24 Months
•Does it hurt when the child urinates?
•Does the child void with increased frequency?
•Does the urine have an unusual odor?
•Has the child had previous urinary tract infections?
•Does the child have a good urinary stream or urine dribbles?
Children Older Than 24 Months
•Does the child have burning on urination?
•Is the child’s urine red or brown?
•Has the child started to wet the bed again?
•Does the child have increased urinary frequency?
•Does the child report abdominal pain?
•Does the child report flank pain?
•Does the child have a fever?
•Does the child have low appetite, or nausea or vomiting?