The management of children with a febrile urinary tract infection seems like a simple topic. However, it is one of the most controversial areas in pediatrics, and over the past decade has seen major developments.
Previously, the way to manage pediatric urinary tract infections (UTI) was with ultrasound (US), nuclear imaging such as dimercaptosuccininc acid (DMSA), or a micturition cystourethrogram (MCUG). The aim was to find all children with vesicoureteric reflux (VUR) or with any uptake defect on the nuclear imaging. Children with VUR of all grades were treated with prophylactic antibiotics.
Children with a febrile UTI were commonly hospitalized for treatment with intravenous (IV) antibiotics. However, during the past decade, critical voices have questioned whether these investigations and aggressive treatments are necessary, and they have advocated for a more selective approach.1
In 2007, the National Institute for Health and Clinical Excellence (NICE) was the first organization to issue international guidelines challenging the status quo for pediatric UTI. These recommendations were controversial and caused a major debate.2,3 The American Academy of Pediatrics (AAP) presented revised guidelines in 2011,4 and they focused primarily on children between the ages of 2 months and 2 years with their first febrile UTI.
Among the most controversial parts in both of these guidelines is the major reduction in how much imaging a child should undergo after the first febrile UTI. The two guidelines are written in quite different formats, but the recommendations are in many ways quite similar. However, the AAP gives the level of evidence, whereas NICE does not.
Both NICE and AAP emphasize that the symptoms of a febrile UTI are very nonspecific, particularly in small children who cannot clearly describe or communicate the pain they are feeling. The clinician assessing a febrile infant with no apparent source for the fever should always consider the possibility of a UTI, and a urine sample should be obtained.
This is not controversial, but the method of urine collection is. There are many challenges to getting a true and reliable urine culture and thus a correct diagnosis of a UTI in a baby or an infant. The chances for both over- and under-diagnosing a UTI are quite high.
Studies comparing bag culture with a suprapubic bladder puncture (SPA) show contamination rates between 7% and 63% when clean voided or bag specimens were compared with SPA.5–7 This is very easy to understand when you look at MCUG pictures from infants, due to basic physiology (see Figure 1 and Figure 2). The urine is easily contaminated with bacteria before it has left the body.
Figure 1: Micturition cystourethrogram in an infant girl showing the flushing of her vagina. Figure courtesy of Kjell Tullus, MD, PhD, FRCPCH.
Figure 2: Micturition cystourethrogram in an infant boy showing the flushing of his prepuce. Figure courtesy of Kjell Tullus, MD, PhD, FRCPCH.
The guidelines from the AAP have taken this information into consideration and now state that bag urine cultures are very unreliable and that they can only be used to rule out a UTI. The guidelines emphasize that a urine specimen obtained by a bag applied to the perineum has an unacceptably high false-positive rate and that they are valid only when they yield a negative result. A positive culture can signify both a true infection or a contaminated culture.
The AAP’s recommendation is that the urine should be obtained either by a suprapubic puncture or by urethral catherization. NICE does not give such recommendations, mainly because in the UK small children with a temperature initially will see their general practitioner, who most likely will be unable to correctly perform any invasive urine test (due to lack of opportunity and practice).
In young women with cystitis, the generally accepted cut level for “significant” bacteriuria (> 105 bacteria/mL) was defined in the 1950s by Edward H. Kass, MD, and was developed for research purposes to ensure that all included women had a true infection. Dr. Kass himself was aware that this cutoff would exclude some women with an infection. Meanwhile, the number of bacteria signifying a true infection has never been formally evaluated in children. Old studies using any positive culture on a suprapubic aspiration (SPA) as gold standard indicate that 19% to 20% of true UTIs diagnosed with SPA showed less than 105 bacteria/mL on the bag culture, leading to the misdiagnoses of there not being a UTI.8,9
The AAP acknowledges that the definition of bacterial numbers in a true UTI is operational and that the former limit of 105 bacteria per mL is not absolute. In an attempt to somewhat overcome this problem, they recommend that a lower threshold of 5 × 104 bacteria per mL should be used. They do appreciate that this change will increase the sensitivity of the culture at the expense of decreased specificity. More children with a contamination will thus be regarded as having true UTIs. NICE has not, as yet, addressed this issue.
A further difficulty in interpreting a urine culture in a small child is that asymptomatic bacteriuria (ABU) occurs quite commonly in infants. This has been shown in a very well-performed population based study from Gothenburg, Sweden, but it is still not as well recognized as it should be.10 This older study provided urine cultures from 3,581 infants born during 1 year in one specific catchment area. All infants had bag cultures done at 2 weeks, 3 months, and 10 months of age. Every child with a positive bag culture had an SPA to confirm if there was any bacterial growth.10
In this population-based study of SPA, confirmed bacteriuria occurred in 2.5% of the boys. In girls, 0.9% showed ABU during their first year of life. None of these children had any symptoms, and all cultures were performed only for research purposes. None of these infants went on to develop a symptomatic UTI.
In the same cohort of children, another 1.2% of the boys and 1.1% of the girls developed an episode of febrile symptomatic UTI. Follow-up showed that the ABU lasted between 0.5 months and 7.5 months (median, 2 months for the girls and 1.5 months for the boys) and cleared spontaneously without out any signs of kidney scarring at 6-year follow-up.10–12
These data indicate that it is difficult to get the correct diagnosis in a febrile infant with ABU. Most pediatricians would rather err on the safe side and make the diagnosis of a febrile UTI and treat it as a symptomatic infection with antibiotics.
The AAP seems to acknowledge these problems and recommends that the diagnosis of a febrile UTI should be based both on a urinalysis showing pyuria and/or bacteriuria and a positive culture. The argument is that children with ABU will have absent or lower leukocyte counts in their urine compared with children with a symptomatic infection. This important diagnostic difficulty is not addressed by NICE. An acute DMSA, which could help define any renal involvement, could be a way to solve this problem. This is neither discussed nor recommended in either set of guidelines.
Importance of Level Diagnosis
To determine whether an infection is a febrile upper UTI (acute pyelonephritis), a lower UTI (cystitis), or ABU, it is important to do a level diagnosis in every case. This is essential because different infections have very different epidemiology and symptoms. They also require different treatment and follow-up. It is akin to how tonsillitis, otitis media, the common cold, and pneumonia cannot all simply be referred to as a “respiratory tract infection” (RTI); the major differences between these separate conditions are key to creating the best outcomes.
A reliable clinical level diagnosis is possible to make in a majority of cases with a UTI. Neither of the two guidelines recommends that any further testing is needed. Many research studies have lumped these three different diagnoses into one, which can explain some inconsistent and biologically difficult-to-believe findings in the literature.
Consequences of Incorrect Diagnosis
The combination of collecting urine with a bag, the use of a fixed cut-off level for a true infection of 105 bacteria per mL, and the risk of misdiagnosing an infant who actually has ABU and a generalized viral infection as having a febrile UTI increases the chances of either a false-positive or false-negative diagnosis of a febrile UTI.
Available epidemiological data indicate one of every four infant boys and one of every six infant girls with true bacteriuria and fever will actually have ABU and another infection as a cause of their temperature. If the urine is collected with a bag or a urine pad, then the chance of contaminated cultures will increase the number of false-positive diagnoses by 7% to 63%.
Both NICE and the AAP agree that oral treatment works as well as IV treatment in infants and children who are not septic and who can reliably take the drug by mouth. Children who need IV treatment should be switched to oral medication as soon as feasible. Neither the AAP nor NICE give any firm recommendations as to which antibiotic should be used, but NICE points out that it should be decided together with the local bacteriological laboratory based on the local bacterial susceptibility patterns. NICE recommends 10 days of treatment, whereas the AAP states that there is no scientific evidence as to whether 7, 10, or 14 days are better.
The AAP recommends that all small children (age 3 months to 2 years) who have had a febrile UTI should undergo a renal and bladder ultrasound (RBUS). NICE is more selective, recommending this only for infants younger than 6 months and in older children if they have an atypical or recurrent UTI. According to NICE, this includes children who are seriously ill, have poor urine flow, or who have an abdominal or bladder mass, raised serum creatinine, septicemia, or failure to respond to treatment with antibiotics within 48 hours of an infection with a non–Escherichia coli organism.
The AAP states that the diagnostic yield from a RBUS is low. Only 1% to 2% of all children will, according to the AAP, have actionable findings, as the use of prenatal US has reduced the prevalence of previously unknown problems.
Both the AAP and NICE recommend that the RBUS should be performed early (within a few days) and only in those with an atypical or very severe infection; the remainder should have the RBUS done within 6 weeks. The reason for this is mainly practical according to NICE guidelines, whereas the AAP states that performing a RBUS too early can be misleading and show acute changes that will resolve spontaneously.
Other Imaging Studies
Both the AAP and NICE recommend a radically reduced number of further investigations. The AAP recommends there not be further imaging in children with first time acute febrile UTI if there are no additional features as indicated by the RBUS, such as hydronephrosis, scarring, or other signs of high-grade VUR or urinary tract obstruction. NICE agrees and recommends an MCUG only in the infants younger than 6 months if they have had an atypical UTI (as defined above). An MCUG, which can reliably diagnose VUR, is not recommended in infants older than 6 months, even in the presence of an atypical infection.
Further evaluation should, according to the AAP, be performed after a recurrent infection. NICE agrees on the need for an MCUG but only in those with recurrences who are still younger than 6 months.
In regard to nuclear imaging (typically DMSA), NICE recommends that to detect uptake defects in the renal parenchyma, this should be done 4 to 6 months after the acute infection in children younger than 3 years who have had a recurrent or an atypical infection. The AAP does not recommend DMSA as part of the routine evaluation of infants after their first febrile UTI, although the AAP does see nuclear scanning as useful in research.
The other radical change in both the NICE and AAP guidelines is that neither recommend the routine use of prophylactic antibiotics, even in children with VUR. When the NICE guidelines were published in 2007, reliable data from randomized controlled trials did not exist on the use of antibiotic prophylaxis in children who had had a UTI. Therefore, the only conclusion that could be made was that prophylaxis could not be routinely recommended.
Since then, six well-designed studies have been performed.13–18 The AAP guidelines, published in 2007, summarize these data in a meta-analyses, showing that the use of antibiotic prophylaxis had no benefit over placebo, even in children with high-grade VUR. However, very few children with grade V VUR were included in the studies. One drawback of this meta-analyses is that boys and girls were analyzed together. The Swedish reflux study clearly showed a difference in that girls with VUR grade III to IV between the age of 2 and 4 years did benefit from prophylactic antibiotic treatment, whereas the boys had too few recurrent infections, even in the placebo group, for the prophylactic antibiotic to make a difference.13
Both the AAP and NICE have presented recommendations to radically reduce imaging in children who have had a febrile UTI. They recommend more imaging after recurrent infections and in those with atypical features of the infection. NICE is more precise than the AAP regarding the definition of an atypical infection. A major reduction of the use of prophylactic antibiotics is also endorsed both in the US and the UK. It is my feeling that we now again have come to a time period with less controversy and more agreement on the management of these children.
- Marks SD, Gordon I, Tullus K. Imaging in childhood urinary tract infections: time to reduce investigations. Pediatr Nephrol. 2008;23(1):9–17 doi:10.1007/s00467-007-0552-9 [CrossRef] .
- Coulthard MG. NICE on childhood UTI: nasty processes produce nasty guidelines. BMJ. 2007;335(7618):463–464 doi:10.1136/bmj.39325.436667.3A [CrossRef] .
- Mori R, Lakhanpaul M, Verrier-Jones K. Diagnosis and management of urinary tract infection in children: summary of NICE guidance. BMJ. 2007;335(7616):395–397 doi:10.1136/bmj.39286.700891.AD [CrossRef] .
- Roberts KBSubcommitte on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610 doi:10.1542/peds.2011-1330 [CrossRef] .
- Al-Orifi F, McGillivray D, Tange S, Kramer MS. Urine culture from bag specimens in young children: are the risks too high?J Pediatr. 2000;137(2):221–226 doi:10.1067/mpd.2000.107466 [CrossRef] .
- Aronson AS, Gustafson B, Svenningsen NW. Combined suprapubic aspiration and clean-voided urine examination in infants and children. Acta Paediatr Scand. 1973;62(4):396–400 doi:10.1111/j.1651-2227.1973.tb08126.x [CrossRef] .
- Etoubleau C, Reveret M, Brouet D, Badier I, et al. Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures. J Pediatr. 2009;154(6):803–806 doi:10.1016/j.jpeds.2009.01.008 [CrossRef] .
- Hansson S, Brandstrom P, Jodal U, Larsson P. Low bacterial counts in infants with urinary tract infection. J Pediatr. 1998;132(1):180–182 doi:10.1016/S0022-3476(98)70512-8 [CrossRef] .
- Koskimies O. Diagnostic accuracy of urinary tract infection and subsequent development of renal scars. J Pediatr. 1995;126(1):157–159 doi:10.1016/S0022-3476(95)70532-5 [CrossRef] .
- Wettergren B, Jodal U. Spontaneous clearance of asymptomatic bacteriuria in infants. Acta Paediatr Scand. 1990;79(3):300–304 doi:10.1111/j.1651-2227.1990.tb11460.x [CrossRef] .
- Wettergren B, Jodal U, Jonasson G. Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand. 1985;74(6):925–933 doi:10.1111/j.1651-2227.1985.tb10059.x [CrossRef] .
- Wettergren B, Hellstrom M, Stokland E, Jodal U. Six year follow up of infants with bacteriuria on screening. BMJ. 1990;301(6756):845–848 doi:10.1136/bmj.301.6756.845 [CrossRef] .
- Brandstrom P, Neveus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010;184(1):292–297 doi:10.1016/j.juro.2010.01.060 [CrossRef] .
- Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med. 2009;361(18):1748–1759 doi:10.1056/NEJMoa0902295 [CrossRef] .
- Garin EH, Olavarria F, Garcia Nieto V, 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(3):626–632 doi:10.1542/peds.2005-1362 [CrossRef] .
- Montini G, Rigon L, Zucchetta P, et al. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008;122(5):1064–1071 doi:10.1542/peds.2007-3770 [CrossRef] .
- Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, Minisini S, Ventura A. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics. 2008; 121(6):e1489–e1494 doi:10.1542/peds.2007-2652 [CrossRef] .
- Roussey-Kesler G, Gadjos V, Idres N, 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(2):674–679 doi:10.1016/j.juro.2007.09.090 [CrossRef] .