D i a g n o s i s an d Management of Urinary Tra c t In f e c t i o n a n d Ve s i c o u re t e r a l R e f lux in t h e N eo n at e Rossana Baracco,
MD,
Tej K. Mattoo,
MD, DCH, FRCP (UK)*
KEYWORDS Neonates Urinary tract infection UTI Vesicoureteral reflux VUR Diagnosis Investigations KEY POINTS Urinary tract infection (UTI) is the most common bacterial infection in febrile newborns. Male newborns, in particular if uncircumcised, are at increased risk of UTI. Clinical presentation of UTI in the newborn is nonspecific, and jaundice may be the only clinical manifestation. Newborns with UTI have a high incidence of congenital anomalies of the kidneys and urinary tract. Prophylaxis with antibiotics is recommended in newborns with vesicoureteral reflux.
EPIDEMIOLOGY AND RISK FACTORS
Urinary tract infection (UTI) is the most common bacterial infection in febrile newborns.1,2 The exact prevalence is difficult to determine, but studies that included infants younger than 2 months reported a prevalence of 4.6% to 7.5%.3–5 Additionally, most of these studies were performed in febrile infants, which could potentially underestimate the true prevalence of UTI in newborns because a large proportion of newborns do not present with fever. A recent study that prospectively evaluated asymptomatic jaundiced infants found that 7.5% of them had a UTI, which is consistent with the findings of the previous studies.6 In premature and low-birth-weight (LBW) infants, the prevalence of UTI can be as high as 20%.7 This high rate may be secondary to hospital-acquired infections and
Disclosures: The authors have no financial interests or conflicts of interest to disclose. Division of Pediatric Nephrology, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Boulevard, Detroit, MI 48201, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol - (2014) -–http://dx.doi.org/10.1016/j.clp.2014.05.011 perinatology.theclinics.com 0095-5108/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
2
Baracco & Mattoo
this population’s increased susceptibility. Premature and LBW infants often require prolonged hospitalizations in neonatal intensive care units and multiple interventions that place them at risk for infection. Mechanical ventilation, parenteral nutrition, intravascular catheters, and associated infectious pathologies have been identified as risk factors for UTI in neonates.8 A strong male predominance is seen in infants younger than 3 months with UTI, mainly because of a higher likelihood of UTI in uncircumcised patients. Absence of circumcision is a well-known risk factor for UTI in male young infants, and increases the risk of UTI by 10-fold.9 Uncircumcised infants have a UTI prevalence of 20.1% compared with 7.5% in female infants and 2.4% in circumcised infants.10 Other risk factors for UTI in newborns are prematurity, white race,11 and renal and urinary tract malformations. Although breast-feeding has been found to protect infants from respiratory and gastrointestinal infections, a recent study showed that it does not protect against UTI in the first 3 months of life.12 VESICOURETERAL REFLUX
Vesicoureteral reflux (VUR) is associated with increased risk of UTI and renal scarring. The grading of VUR, which was standardized in 198213 by using the radiographic voiding cystourethrogram (VCUG), divides VUR into 5 grades, with grade 5 being the most severe (Fig. 1). Vesicoureteral reflux is the most common congenital urinary tract abnormality in children, including neonates. In a study exclusively involving 45 male neonates with UTI, 43.0% had VUR.14 In another study of 95 patients younger than 4 months and hospitalized with UTI, VUR was diagnosed in 31.7% of patients.15 In a study that evaluated the gender distribution of VUR, the incidence of VUR was equal at 20% among male and female neonates with UTI, even though the incidence of UTI was 6 times more common in boys. The same study also reported that the VUR was diagnosed at a 4-fold higher rate in neonates with Klebsiella-induced UTI compared with those with Escherichia Coli–induced UTI.16 The incidence of VUR
Fig. 1. International reflux study grading scheme. Grade 1, reflux into nondilated ureter. Grade 2, reflux into the renal pelvis and calyces without dilatation. Grade 3, mild/moderate dilatation of ureter and pelvicalyceal system. Grade 4, dilation of the renal pelvis and calyces with moderate ureteral tortuosity, blunting of fornices. Grade 5, gross dilatation of the ureter, pelvis, and calyces; ureteral tortuosity; loss of papillary impressions. (Adapted from Lebowitz RL, Olbing H, Parkkulainen KV, et al. International system of radiographic grading of vesicoureteric reflux. Pediatr Radiol 1985;15(2):106; with permission.)
Diagnosis and Management of UTI and VUR
seems to be lower in preterm neonates than in full-term neonates with UTI. In a study of 118 hospitalized preterm infants younger than 2 months, a major abnormality was found on at least one imaging study for 4% (5 of 118) of infants and on 4% of renal ultrasounds and 2% of VCUG examinations.17 In most neonates, VUR is diagnosed after an episode of UTI (primary VUR), although in many it is diagnosed during follow-up for antenatally diagnosed congenital anomalies of the kidney and urinary tract (CAKUT), such as multicystic dysplastic kidney, renal agenesis, or ureteral ectopia. Approximately 10% of patients, mostly boys, with antenatally diagnosed hydronephrosis (antenatal VUR) are found to have VUR during routine postnatal follow-up.18 Vesicoureteral reflux can also occur secondary to bladder outlet obstruction or neurogenic bladder (secondary VUR). VUR AND RENAL SCARRING
Vesicoureteral reflux increases the risk of UTI and renal scarring, which is called reflux nephropathy. The presence of reflux nephropathy puts affected patients at higher risk of developing hypertension, proteinuria, and progression of renal disease later in life. Renal scarring that occurs because of acute pyelonephritis is called acquired reflux nephropathy, as opposed to the renal scarring that may be present from birth, even before the occurrence of UTI, which is called congenital reflux nephropathy.19 The current gold standard for diagnosing renal scarring is a technetium-99m-labeled dimercaptosuccinic acid (DMSA) renal scan, which should be performed a few months after acute infection, only if clinically indicated. Routine DMSA renal scans have no role in the acute management of UTI in neonates. CAUSATIVE ORGANISMS FOR UTI
Although traditionally the source of infection in neonatal UTI has been thought to be hematogenous, the microbiology of the infections makes ascending infection from the urethra the most likely source. Vesicoureteral reflux predisposes to pyelonephritis. The most common bacterial pathogen identified in neonatal UTI is E coli (80%–88% of cases),9,20,21 followed by Enterobacter spp and Klebsiella pneumonia. Other less common pathogens include Pseudomonas aeruginosa, Enterococcus spp, group B streptococcus, Staphylococcus aureus, Citrobacter freundii, Serratia marcescens, and K oxytoca. The less common bacterial pathogens are more frequent in neonates who acquire a UTI in the hospital. Fungal UTI is predominantly found in nosocomial UTI and is mainly caused by Candida spp.22 CLINICAL PRESENTATION
The symptoms of UTI in a newborn infant are generally nonspecific and similar to those seen in the clinical presentation of neonatal sepsis.22 Young infants with high fever (39 C) are more likely to have a UTI.9 However, newborns with a UTI do not always present with fever. In fact, as many as half of the neonates with a UTI may have only low-grade fever or none at all.7 Other associated symptoms of UTI in neonates include poor feeding, failure to thrive, vomiting, diarrhea, prolonged jaundice, lethargy, and irritability. Jaundice in the absence of any other symptoms or indications has been identified as a presenting sign of UTI in neonates.6 Newborns with UTI are at a higher risk for bacteremia than older infants. Bachur and Caputo23 found that bacteremia associated with UTI in infants is inversely related to age. The rate of bacteremia in neonates with UTI varies in different studies. Ginsburg and
3
4
Baracco & Mattoo
colleagues24 found positive blood culture results in 31% of neonates with UTI. Other studies have reported lower rates of 4%21 to 6%.4 This discrepancy is likely because of the differences in study populations, including age group; hospital setup; and institutional protocols in infants with fever. Neonates with hospital-acquired UTI have a higher risk of bacteremia than neonates who present with a UTI from home (communityacquired). Lopez Sastre and colleagues22 found that 24.2% of neonates who acquired a UTI in the hospital had positive blood culture results, compared with 10.8% of neonates with a community-acquired UTI (P20%
ESR >30%
Sensitivity
54–82
82.0–96.0
64–85
59
73
Specificity
92–98
94.0
63–99
90
78
PPV
45
NPV
97
11 99.7
99
Abbreviations: C-RP, C-reactive protein; ESR, erythrocyte sedimentation rate; NPV, negative predictive value; PPV, positive predictive value; UA, urinalysis. Data from Refs.1,2,28,29,31
Diagnosis and Management of UTI and VUR
The gold standard for diagnosing UTI is a positive urine culture for a single organism. A positive culture is defined as growth of 10,000 or more colony-forming units (CFU) per milliliter if the urine is obtained using suprapubic aspiration, or 100,000 CFU/mL or more if it is obtained through catheterization.2,11 Although some studies suggest that urine cultures obtained with catheterization of the bladder that grow 10,000 to 50,000 CFU/mL may represent asymptomatic bacteriuria,27 other studies have shown that as many as 20% of infants younger than 12 months with symptomatic UTI show low bacterial counts (
MD,
Tej K. Mattoo,
MD, DCH, FRCP (UK)*
KEYWORDS Neonates Urinary tract infection UTI Vesicoureteral reflux VUR Diagnosis Investigations KEY POINTS Urinary tract infection (UTI) is the most common bacterial infection in febrile newborns. Male newborns, in particular if uncircumcised, are at increased risk of UTI. Clinical presentation of UTI in the newborn is nonspecific, and jaundice may be the only clinical manifestation. Newborns with UTI have a high incidence of congenital anomalies of the kidneys and urinary tract. Prophylaxis with antibiotics is recommended in newborns with vesicoureteral reflux.
EPIDEMIOLOGY AND RISK FACTORS
Urinary tract infection (UTI) is the most common bacterial infection in febrile newborns.1,2 The exact prevalence is difficult to determine, but studies that included infants younger than 2 months reported a prevalence of 4.6% to 7.5%.3–5 Additionally, most of these studies were performed in febrile infants, which could potentially underestimate the true prevalence of UTI in newborns because a large proportion of newborns do not present with fever. A recent study that prospectively evaluated asymptomatic jaundiced infants found that 7.5% of them had a UTI, which is consistent with the findings of the previous studies.6 In premature and low-birth-weight (LBW) infants, the prevalence of UTI can be as high as 20%.7 This high rate may be secondary to hospital-acquired infections and
Disclosures: The authors have no financial interests or conflicts of interest to disclose. Division of Pediatric Nephrology, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Boulevard, Detroit, MI 48201, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol - (2014) -–http://dx.doi.org/10.1016/j.clp.2014.05.011 perinatology.theclinics.com 0095-5108/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
2
Baracco & Mattoo
this population’s increased susceptibility. Premature and LBW infants often require prolonged hospitalizations in neonatal intensive care units and multiple interventions that place them at risk for infection. Mechanical ventilation, parenteral nutrition, intravascular catheters, and associated infectious pathologies have been identified as risk factors for UTI in neonates.8 A strong male predominance is seen in infants younger than 3 months with UTI, mainly because of a higher likelihood of UTI in uncircumcised patients. Absence of circumcision is a well-known risk factor for UTI in male young infants, and increases the risk of UTI by 10-fold.9 Uncircumcised infants have a UTI prevalence of 20.1% compared with 7.5% in female infants and 2.4% in circumcised infants.10 Other risk factors for UTI in newborns are prematurity, white race,11 and renal and urinary tract malformations. Although breast-feeding has been found to protect infants from respiratory and gastrointestinal infections, a recent study showed that it does not protect against UTI in the first 3 months of life.12 VESICOURETERAL REFLUX
Vesicoureteral reflux (VUR) is associated with increased risk of UTI and renal scarring. The grading of VUR, which was standardized in 198213 by using the radiographic voiding cystourethrogram (VCUG), divides VUR into 5 grades, with grade 5 being the most severe (Fig. 1). Vesicoureteral reflux is the most common congenital urinary tract abnormality in children, including neonates. In a study exclusively involving 45 male neonates with UTI, 43.0% had VUR.14 In another study of 95 patients younger than 4 months and hospitalized with UTI, VUR was diagnosed in 31.7% of patients.15 In a study that evaluated the gender distribution of VUR, the incidence of VUR was equal at 20% among male and female neonates with UTI, even though the incidence of UTI was 6 times more common in boys. The same study also reported that the VUR was diagnosed at a 4-fold higher rate in neonates with Klebsiella-induced UTI compared with those with Escherichia Coli–induced UTI.16 The incidence of VUR
Fig. 1. International reflux study grading scheme. Grade 1, reflux into nondilated ureter. Grade 2, reflux into the renal pelvis and calyces without dilatation. Grade 3, mild/moderate dilatation of ureter and pelvicalyceal system. Grade 4, dilation of the renal pelvis and calyces with moderate ureteral tortuosity, blunting of fornices. Grade 5, gross dilatation of the ureter, pelvis, and calyces; ureteral tortuosity; loss of papillary impressions. (Adapted from Lebowitz RL, Olbing H, Parkkulainen KV, et al. International system of radiographic grading of vesicoureteric reflux. Pediatr Radiol 1985;15(2):106; with permission.)
Diagnosis and Management of UTI and VUR
seems to be lower in preterm neonates than in full-term neonates with UTI. In a study of 118 hospitalized preterm infants younger than 2 months, a major abnormality was found on at least one imaging study for 4% (5 of 118) of infants and on 4% of renal ultrasounds and 2% of VCUG examinations.17 In most neonates, VUR is diagnosed after an episode of UTI (primary VUR), although in many it is diagnosed during follow-up for antenatally diagnosed congenital anomalies of the kidney and urinary tract (CAKUT), such as multicystic dysplastic kidney, renal agenesis, or ureteral ectopia. Approximately 10% of patients, mostly boys, with antenatally diagnosed hydronephrosis (antenatal VUR) are found to have VUR during routine postnatal follow-up.18 Vesicoureteral reflux can also occur secondary to bladder outlet obstruction or neurogenic bladder (secondary VUR). VUR AND RENAL SCARRING
Vesicoureteral reflux increases the risk of UTI and renal scarring, which is called reflux nephropathy. The presence of reflux nephropathy puts affected patients at higher risk of developing hypertension, proteinuria, and progression of renal disease later in life. Renal scarring that occurs because of acute pyelonephritis is called acquired reflux nephropathy, as opposed to the renal scarring that may be present from birth, even before the occurrence of UTI, which is called congenital reflux nephropathy.19 The current gold standard for diagnosing renal scarring is a technetium-99m-labeled dimercaptosuccinic acid (DMSA) renal scan, which should be performed a few months after acute infection, only if clinically indicated. Routine DMSA renal scans have no role in the acute management of UTI in neonates. CAUSATIVE ORGANISMS FOR UTI
Although traditionally the source of infection in neonatal UTI has been thought to be hematogenous, the microbiology of the infections makes ascending infection from the urethra the most likely source. Vesicoureteral reflux predisposes to pyelonephritis. The most common bacterial pathogen identified in neonatal UTI is E coli (80%–88% of cases),9,20,21 followed by Enterobacter spp and Klebsiella pneumonia. Other less common pathogens include Pseudomonas aeruginosa, Enterococcus spp, group B streptococcus, Staphylococcus aureus, Citrobacter freundii, Serratia marcescens, and K oxytoca. The less common bacterial pathogens are more frequent in neonates who acquire a UTI in the hospital. Fungal UTI is predominantly found in nosocomial UTI and is mainly caused by Candida spp.22 CLINICAL PRESENTATION
The symptoms of UTI in a newborn infant are generally nonspecific and similar to those seen in the clinical presentation of neonatal sepsis.22 Young infants with high fever (39 C) are more likely to have a UTI.9 However, newborns with a UTI do not always present with fever. In fact, as many as half of the neonates with a UTI may have only low-grade fever or none at all.7 Other associated symptoms of UTI in neonates include poor feeding, failure to thrive, vomiting, diarrhea, prolonged jaundice, lethargy, and irritability. Jaundice in the absence of any other symptoms or indications has been identified as a presenting sign of UTI in neonates.6 Newborns with UTI are at a higher risk for bacteremia than older infants. Bachur and Caputo23 found that bacteremia associated with UTI in infants is inversely related to age. The rate of bacteremia in neonates with UTI varies in different studies. Ginsburg and
3
4
Baracco & Mattoo
colleagues24 found positive blood culture results in 31% of neonates with UTI. Other studies have reported lower rates of 4%21 to 6%.4 This discrepancy is likely because of the differences in study populations, including age group; hospital setup; and institutional protocols in infants with fever. Neonates with hospital-acquired UTI have a higher risk of bacteremia than neonates who present with a UTI from home (communityacquired). Lopez Sastre and colleagues22 found that 24.2% of neonates who acquired a UTI in the hospital had positive blood culture results, compared with 10.8% of neonates with a community-acquired UTI (P20%
ESR >30%
Sensitivity
54–82
82.0–96.0
64–85
59
73
Specificity
92–98
94.0
63–99
90
78
PPV
45
NPV
97
11 99.7
99
Abbreviations: C-RP, C-reactive protein; ESR, erythrocyte sedimentation rate; NPV, negative predictive value; PPV, positive predictive value; UA, urinalysis. Data from Refs.1,2,28,29,31
Diagnosis and Management of UTI and VUR
The gold standard for diagnosing UTI is a positive urine culture for a single organism. A positive culture is defined as growth of 10,000 or more colony-forming units (CFU) per milliliter if the urine is obtained using suprapubic aspiration, or 100,000 CFU/mL or more if it is obtained through catheterization.2,11 Although some studies suggest that urine cultures obtained with catheterization of the bladder that grow 10,000 to 50,000 CFU/mL may represent asymptomatic bacteriuria,27 other studies have shown that as many as 20% of infants younger than 12 months with symptomatic UTI show low bacterial counts (
