Review Urinary tract infections in children Kjell Tullus, Nader Shaikh Urinary tract infections (UTIs) in children are among the most common bacterial infections in childhood. They are equally common in boys and girls during the first year of life and become more common in girls after the first year of life. Dividing UTIs into three categories; febrile upper UTI (acute pyelonephritis), lower UTI (cystitis), and asymptomatic bacteriuria, is useful for numerous reasons, mainly because it helps to understand the pathophysiology of the infection. A single episode of febrile UTI is often caused by a virulent Escherichia coli strain, whereas recurrent infections and asymptomatic bacteriuria commonly result from urinary tract malformations or bladder disturbances. Treatment of an upper UTI needs to be broad and last for 10 days, a lower UTI only needs to be treated for 3 days, often with a narrow-spectrum antibiotic, and asymptomatic bacteriuria is best left untreated. Investigations of atypical and recurrent episodes of febrile UTI should focus on urinary tract abnormalities, whereas in cases of cystitis and asymptomatic bacteriuria the focus should be on bladder function. Urinary tract infections (UTIs) are common bacterial infections in children, affecting around 1·7% of boys and 8·4% of girls before the age of 7 years.1 During the first year of life UTIs affect boys and girls equally, but after that age most cases occur in girls (figure 1).2 Symptoms of a UTI are quite diverse, ranging from no symptoms to a severely unwell child with a high temperature and sometimes secondary bacteraemia.3 UTIs can be divided into three different categories; acute pyelonephritis (kidney infection), acute cystitis (bladder infection), and asymptomatic bacteriuria.4 Although there are cases that cannot be easily categorised, this subdivision has been helpful in making diagnostic and management decisions. Patients with acute pyelonephritis generally present with a high temperature. Older children can show flank pain which in younger children is seen as stomach pain. The symptoms of acute cystitis in children are generally similar to those seen in adult patients—including pain when urinating, increased frequency and urgency to urinate, and sometimes pain in the lower part of the stomach. However, children with these symptoms usually do not have a fever. The table summarises the diagnostic accuracy of various demographic, clinical, and laboratory factors in the diagnosis of UTIs. A calculator (UTICalc) that uses a combination of the most useful findings to estimate the probability of a UTI in children younger than 2 years is available online. Children with asymptomatic bacteriuria often show symptoms related to bladder dysfunction but not to bacteriuria. Diagnosis The clinical diagnosis of a UTI is based on symptoms and confirmed growth of bacteria in the urine. Other findings in the urine such as leucocyturia and a positive nitrite test are generally used to support the diagnosis. Absence of leucocytes in the urine can be used to rule out a UTI in the acute setting if there are no other strong indicators of a UTI; however, obtaining a urine culture seems wise because some children without leucocyturia might still have a UTI. Blood tests, particularly for Renal Unit, Great Ormond Street Hospital for Children, London, UK (K Tullus MD); and Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA (Prof N Shaikh MD) Correspondence to: Dr Kjell Tullus, Renal unit, Great Ormond Street Hospital for Children, London WC1N 3JH, UK [email protected] inflammatory markers, and nuclear imaging have been used to localise the infection. However, more accurate markers for acute pyelonephritis are still needed. Bacteriuria is an obligatory finding in any UTI case,6,7 typically with growth of 10⁵ colony forming units (CFU)/mL or more of gram-negative bacteria originating from the faecal flora.8 Escherichia coli is found in 80–90% of cases. There are however some problems with detecting Search strategy and selection criteria We searched the literature to identify studies and reviews relevant to the scope of this Review. Searches were done in the following databases: Health Technology Assessment database, MEDLINE. We used the search terms “urinary tract”, “urinary tract infections”, “UTI”, “upper and lower”, “cystitis”, “proteinuria”, “albuminuria”, “bacteriuria”, “pyuria”, “vesicourethral reflux”, “VUR”, and “pyelonephritis”. We looked at all literature published between 1962 and 2020. A For the UTICalc see https://uticalc.pitt.edu B 180 Girls (n-952) Boys (n=225) Pyelonephritis Cystitis UTI unspecified 160 140 Number of patients Introduction Lancet 2020; 395: 1659–68 120 100 80 60 40 20 0 0 2 4 6 Age (years) 8 10 0 2 4 6 8 10 Age (years) Figure 1: Occurrence of UTIs according to age (A) Occurrence of UTIs in girls. (B) Occurrence of UTIs in boys. UTI=urinary tract infection. Reproduced from Winberg and colleagues,2 by permission of John Wiley and Sons. www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. 1659 Review Diagnosis Likelihood ratios* UTI (n=542) No UTI (n=1144) Positive likelihood ratio (CI) Negative likelihood ratio (CI) Age (<12 months) 431 798 1·14 (1·08–1·21) 0·68 (0·56–0·82) Female 483 733 1·39 (1·32–1·47) 0·30 (0·24–0·39) Non-black race 461 786 1·24 (1·17–1·30) 0·47 (0·37–0·58) Fever (≥48 h) 238 327 1·52 (1·33–1·73) 0·78 (0·72–0·85) No other source of fever 443 602 1·55 (1·45–1·66) 0·39 (0·32–0·47) Maximum reported temperature (≥39°C) 336 455 1·41 (1·29–1·55) 0·65 (0·57–0·74) Foul smelling urine 42 12 7·39 (3·92–13·92) 0·93 (0·91–0·96) History of UTIs 35 28 2·64 (1·62–4·29) 0·96 (0·94–0·98) Uncircumcised male 31 42 4·94 (3·45–7·07) 0·45 (0·32–0·63) 0·99 (0·93–1·05) Vomiting 142 291 1·03 (0·87–1·23) Diarrhoea 76 188 0·85 (0·67–1·09) 1·03 (0·99–1·07) 6 16 0·79 (0·31–2·01) 1·00 (0·99–1·01) Abdominal tenderness on examination Leucocyte esterase (≥ trace) 504 82 12·9 (10·5–16·0) 0·07 (0·05–0·10) Positive nitrite test 200 26 16·1 (10·9–24·0) 0·65 (0·61–0·69) WBC per mm³ (≥10) 383 77 10·1 (8·11–12·5) 0·11 (0·08–0·15) UTI=urinary tract infection. WBC=white blood cell. *The larger the positive likelihood ratio the more useful the finding is in ruling in a UTI. The smaller the negative likelihood ratio, the more useful the finding is in ruling out a UTI. Table: Accuracy of findings in the diagnosis of UTIs5 bacteriuria in children. Contamination by the preputial or vaginal flora is a pronounced problem.9 Studies comparing culture results from a concomitant bladder puncture compared with bag collection of urine show a 25% contamination rate.10 A urinary catheter to obtain samples is commonly used in some countries and markedly improves the diagnostic accuracy compared with bag urine cultures.11 A suprapubic bladder puncture gives the most accurate culture result but because of its invasive nature, it is not used in many countries. Another problem was identified in a 2016 study of 7163 children in general practice in the UK.12 Markedly different results were found when the same urine was sent to two different bacteriological laboratories. The difference was substan­ tial; the National Health Service laboratory reported positive cultures in 6·6% of children younger than 3 years and 3·2% in children 3 years and older, whereas the research laboratory reported positive cultures in 1·8% and 1·9%, respectively.12 A further difficulty is that in young children with proven UTIs, around 20% of cultures show lower bacterial numbers than the generally used cutoff of 10⁵ CFU/mL.13,14 False negative results can be decreased by lowering the cutoff point. The American Academy of Pediatrics (AAP) now recommends using a cutoff of 5 × 10⁴ CFU/mL for samples obtained by catheterisation; 10⁴ CFU/mL is used in many countries and is also now gaining favour in the USA.7,15 However, this increased sensitivity does have a disadvantage of reduced specificity—ie, a larger number of false positive results. Several guidelines recommend different cutoff points for urine specimens obtained by 1660 suprapubic bladder puncture or urethral catheterisation. In suprapubic specimens most guidelines accept any growth of bacteria as significant. Approximately 0·5 % of all infants display asymptomatic bacteriuria at any given time during their first year of life.16,17 Separating those infants from children with a true UTI is difficult when they are presenting with a fever, because the fever can be from a viral infection. The problem with overdiagnosis and underdiagnosis is thus clinically important and partly explains why imaging in children can show post-infectious renal scars in the absence of any diagnosed febrile UTI. Leucocyturia is found in most children with a UTI and is regarded by the AAP as a prerequisite to make the diagnosis.7 However, it has been shown that at least 10% of children with a UTI do not have white blood cells or leucocyte esterase present in their urine, which is especially true in UTI cases caused by organisms other than E coli.18,19 Most children with a fever and an infection outside of the urinary tract also have leucocyturia; thus, both the sensitivity and specificity of the test are low.19,20 A recent study21 suggested that the requirement of leucocyturia for the diagnosis of a UTI can lead to more harm than good (ie, 12 missed UTI cases to prevent one unnecessary antibiotic prescription) which argues for a change to the way the AAP defines a UTI diagnosis. A nitrite test has a very high specificity to diagnose bacteriuria and is commonly used to diagnose UTIs. However, the sensitivity of this test is only about 50%.19 Not all bacteria produce nitrite and this process takes some time. Frequent bladder emptying, as is common­place in infants, can thus give a false negative nitrite test result. C-reactive protein, procalcitonin, and ESR have been advocated for the diagnosis of acute pyelonephritis. However, studies show marked heterogeneity in the accuracy of these tests. Low C-reactive protein concen­ tration can be useful in excluding acute pyelonephritis.22 Whereas, procalcitonin seems to help to diagnose a child with acute pyelonephritis.23 In some centres, dimercaptosuccinic acid (DMSA) scans are used to diagnose renal involvement in a UTI. An uptake defect on the renal isotope scan found during the first few weeks after the infection is indicative of pyelonephritis (figure 2). However, most national guide­ lines do not recommend routine use of DMSA scans because of the inconvenience, high cost, and radiation exposure. Risk factors for UTIs in children UTIs develop from an imbalance between bacterial virulence and host defence. These factors vary in different kinds of UTIs. P-fimbriated E coli virulence factors have been well studied.24 Fimbriae help bacteria attach to the uroepithelial cell lining and thereby remain in the urinary tract despite the flow of urine (figure 3).25 Uropathogenic bacteria also have a range of other virulence factors that enable them to cause infection. These factors include www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. Review haemolysin, a specific protective O antigen on the carbohydrate end of the lipopolysaccharide, capsule K phenotypes, and different siderophores enabling the bacteria to get essential nutrient iron.26 Other bacterial species such as Klebsiella and Pseudomonas do not have such abilities and often rely on impaired host defence to cause an infection. Urine flow is an important host defence factor in the urinary tract. Obstructing uropathies and severe vesicoureteral reflux (VUR) markedly increases the chance of a UTI. Altered host defences can be a risk factor for UTIs. Some parts of the innate immune system such as the number of toll-like receptors or the production of antibacterial peptides (eg, cathelicidin and α-defensin) have been suggested to influence the risk of developing a UTI, and independent studies to support this finding are awaited.27–29 The acquired immune response does not seem to play a dominant role in the protection against a UTI by contrast with other niches in the body,30 and children with immunodeficiencies rarely get UTIs. Additionally, functional bladder and bowel dysfunction also seems to play an important role in the pathophysiology of UTIs.31 Figure 2: Dimercaptosuccinic acid scintigraphy On the left a kidney with several uptake defects. On the right a kidney with normal uptake of dimercaptosuccinic acid. UTI treatment Treatment of a UTI should be guided by the presenting symptoms, the child’s previous medical history, and the resistance patterns of uropathogens in the area where the child lives. The antimicrobial treatment should also be tailored to the location of the UTI. Acute pyelonephritis Children with acute pyelonephritis are febrile and typically ill-appearing and should immediately be started on antibiotic treatment after having their urine sent for culture. Two meta-analyses32,33 from the Cochrane group showed that oral antibiotics as an initial treatment are as effective as 3–4 days of intravenous antibiotics followed by oral treatment. However, children with sepsis or those who vomit too much to take oral antibiotics would need initial intravenous treatment.34 The type of antibiotic to use should be decided on the basis of the child’s previous medical history. Previously healthy children should be given broad spectrum antibiotics chosen on the basis of knowledge of the local pattern of antibiotic resistance.3 Children with known urinary tract malformations who have had frequent contact with hospitals need a broader anti­ biotic. Children on antibiotic prophylaxis should be assumed to be infected with a bacterium resistant to that drug.35 The response to treatment should be evaluated at 36–48 h when most children show substantial improvement and parents should be told to bring back their child for a re-evaluation if improvement does not occur. The most common causes for treatment failure include incorrect diagnosis, resistant bacteria, renal abscess, and malformations of the urinary tract. Figure 3: P-fimbriated Escherichia coli attaching to the ureteral surface An image taken by a scanning electron microscope. The arrow points to the attached E coli. Image courtesy of James Roberts (Tulane University, New Orleans, LA, USA). Acute cystitis Treatment in children with cystitis can be done by giving a less broad spectrum antibiotic such as nitrofurantoin or trimethoprim. The duration of treatment should be shorter, and even a one-dose treatment has been advocated. However, a meta-analysis showed that a 1-day www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. 1661 Review course had a slightly worse clinical outcome compared with a 3-day course.36 A large trial is currently under­ way to study short-course therapy for UTIs further (NCT01595529). Asymptomatic bacteriuria Asymptomatic bacteriuria is a controversial topic and data on this topic are sparse. A meta-analysis found that the prevalence of asymptomatic bacteriuria was 0·37% (95% CI 0·09–0·82) in boys and 0·47% (0·36–0·59) in girls (much lower than the often cited values of 1–2%).21 For increased clarity asymptomatic bacteriuria can be discussed as three different conditions depending on age and any underlying urinary tract malformation. The first group of children are girls aged between 3 years and 10 years who have recurrent UTIs and, when tested between episodes, often have asymptomatic bacteriuria. However, even during the asymptomatic period, these girls often display symptoms of functional bladder and bowel dysfunction (eg, wetting, urgency, constipation).37 Accordingly, the term covert bacteriuria has there­ fore been suggested by some authors instead of asymptomatic bacteriuria.36 Bacteriuria can be eradi­ cated with antibiotics but symptoms often persist. The chance of recurrent bacteriuria is high (80% within 12 months).38 The recurrent bacteria can, depending on their virulence properties, cause more pronounced symptoms and in 15% of patients even acute pyelonephritis. Controlled trials do not support treatment for covert bacteriuria.39,40 Studies also suggest that asymptomatic bacteriuria can protect against the development of symptomatic UTI. Bacteria causing asymptomatic bacteriuria do become avirulent over time.41 However, because differentiating covert bac­ teriuria from a UTI is difficult, especially in children with ongoing symptoms of bladder and bowel dysfunction, assembling a repre­ sentative cohort of children for prospective follow-up is challenging. As such, the results need to be interpreted with these limitations in mind. Asymptomatic bacteriuria during the first year of life, in which uncircumcised male babies are in the highest risk group, has been investigated in only a few studies.21 In a population-based study, 3581 children were inves­ tigated using bladder puncture at three timepoints during their first year of life.16 Although the cumulative prevalence of bacteriuria during the study period was 2·5% in boys and 0·9% in girls, the point prevalence was less than 0·5% at any one of the three timepoints. Asymptomatic bacteriuria was the most prevalent in uncircumcised boys younger than 2 months and generally resolved spontaneously.16 Children with asymptomatic bacteriuria did not develop febrile UTIs.42 Additionally, children with genitourinary abnormalities or a neurogenic bladder often have bacteriuria without symptoms. We have not included children with these conditions in this Review. 1662 Long-term outcomes of renal scarring Knowledge of long-term outcomes for children with a febrile UTI is essential as the fear of severe long-term complications has been the main driver for radiological investigation and the previously recommended longterm antimicrobial prophylaxis. Renal scarring is a controversial topic with disparate views among paediatricians.43 The interpretation of literature is complicated by several issues. The definition of renal scarring is not always uniformly applied and the distinction between congenital and post-infectious scars is sometimes difficult.6 An additional problem is that most studies are based on groups of patients from tertiary centres. Long-term follow-up of children is needed to find out the full long-term effect of infectioninduced kidney damage. The most reliable population-based study with long-term follow-up included cohorts of children from Sweden (Gothenburg), who had UTIs with scarring on urography imaging that was done in the 1970s.2 These cohorts were recalled for renal function studies 16–26 years later and results showed fewer long-term complications related to renal scarring than reported by other studies. Notably, these good long-term results are seen in a country with a strong practice of early and accurate diagnosis of febrile UTIs in children. The situation can be different in other parts of the world and long-term data from other populations are still needed. There are three important sequelae of renal scarring: reduced kidney function, hypertension, and pregnancy complications. Toffolo and colleagues44 reviewed longterm outcome data from 19 studies of 3148 children. Follow-up time varied between 6 months and 41 years. The prevalence of impaired kidney function ranged from 0% to 56%, reflecting a great heterogeneity between studies. Of the eight prospective studies, only two were population based. Of the 1029 children, chronic kidney disease was present in 55 and 43 of those children already showed chronic kidney disease symptoms at the start of follow-up. Toffollo and others44 thus summarised that only 0·4% of monitored children with a normal glomerular filtration rate (GFR) at initial contact showed a decreased renal function at follow-up. Two different cohorts from Sweden show the longest prospective follow-up. Martinell and colleagues45 studied women who had a UTI during their childhood. No significant difference in GFR was found for women with mild or moderate scarring. In 2015, Geback and colleagues46 extended the follow-up of this cohort to a mean age of 41 years. The GFR in women with bilateral renal scarring had gone down from 93 mL/min/1·73 m² at infancy to 81 mL/min/1·73 m² (p=0·01) at age of 41 years, whereas GFR had remained stable in those without any scars. There is a chance that a small group of these individuals with bilateral scarring might develop clinically significant chronic kidney disease over the next few decades. www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. Review Wennerstrom and others47 followed-up on 1221 children consecutively for a median of 22 years after their first non-obstructive UTI occurred in childhood. None of the individuals had developed impaired kidney function, except for a small group of seven people with bilateral renal scarring whose GFR was 84 mL/min/1·73 m², which was lower than the GFR of those with unilateral scarring (p=0·007).47 The median urine albumin creatinine ratio was low in both groups. The long-term outcomes for blood pressure in individuals with renal scarring was also reviewed by Toffolo and colleagues.44 Again the published studies were heterogeneous. 17 of the 19 reviewed studies had variable quality, with only five studies reporting blood pressure at participant recruitment. At the end of followup, the prevalence of hypertension varied between 1·2% and 35%. The Martinell and colleagues45 cohort showed that three of 54 women (6%) had hypertension at the first follow-up after a median of 15 years. Geback and others48 did a further follow-up after 35 years and found that 38% (22 of 58) women with scarring had hypertension compared with 14% (four of 28 women) in those without kidney scars. Ambulatory blood pressure measurements differed significantly with higher systolic blood pressure in the group with kidney scarring (by 3 mm Hg during the day and 5 mm Hg at night). Whereas, in the other Swedish cohort from Gothenburg,49 there was no difference found in the 24 h blood pressure between patients with and without renal scars. In the Toffolo and colleagues44 review of pregnancy outcomes in women with renal scarring, findings between studies were also very different. Five studies included data from 282 pregnancies in 159 women. Hypertension, pro­teinuria, or pre-eclampsia occurred in 12% (34) of these pregnancies. Martinell and colleagues50 monitored 65 pregnancies in 41 women and did not find a statistically increased risk of serious complications for the mothers or the children. VUR VUR is the retrograde flow of urine from the bladder up into the upper urinary tract during bladder contraction. VUR is graded on a scale of I (mild) to V (severe); 95% of VUR in children range from grades I to III.51 VUR, and in particular dilating high grade VUR (grade IV or V), is regarded as a risk factor for recurrent UTIs and is directly linked with renal scarring. VUR is usually present in children with congenital renal dysplasia often called Congenital Abnormalities of the Kidneys and Urinary Tract (CAKUT); in some of these cases VUR does not cause renal scarring, but is merely associated with it. Children with VUR have an increased risk of renal scarring (risk ratio of 2·6) compared with children without VUR. This risk increases with increasing grades of VUR (odds of kidney damage around 20 times higher in children with VUR stage IV-V compared with those with VUR stage I-II).51 Epidemiology of VUR Approximately 30% of young children with their first febrile UTI have VUR.34 However, how common VUR is in the healthy population remains unclear. Studies examining healthy children are all over 60 years old and because of ethical reasons they are unlikely to be repeated.52 These studies showed that only a few (2%) of the investigated children had reflux. However, the last study examining healthy children published in 1967 did show a strikingly different result; 65% (11 of 17) of healthy infants had reflux during their first 6 months of life.53 Two Finnish studies54,55 took a different approach and retrospectively studied the prevalence of VUR in 2036 and 406 children with an initial diagnosis of a UTI. These children had a micturating cystourethrogram done because of a suspected febrile UTI. These children were stratified into those with and without a UTI on the basis of the results from the urine dipstick and urine culture. VUR was present in 28–40% of children regardless of whether a UTI was diagnosed. This finding was also true for VUR graded III-V that was found in 15–20% of the children regardless of them having a true UTI.54,55 VUR spontaneously resolves in most children several years after detection. Bilateral high-grade VUR resolves less quickly and sometimes not at all (figure 4).56 VUR is clearly a risk factor for recurrent UTIs and renal scarring, particularly high grade VUR. However, VUR is neither necessary nor sufficient for the development of renal scars.57 Screening for VUR in children with their first UTI is no longer advocated in most countries. Proponents argue that VUR is a treatable condition that increases the risk of recurrent febrile UTIs. Opponents argue that the inconvenience and risks of investigating for VUR outweigh any potential benefits. Treating children with VUR Treatment of children with VUR is controversial. Three options are available: correcting the VUR with surgery, using long-term antimicrobial prophylaxis, or careful monitoring of the child. Surgically there are two options available: reimplantation of the ureters or injection of a bulking agent below the ureteric orifice. The success rate for these two methods in reducing VUR varies. Surgery typically cures 92–98% of cases,58 although the success of injection depends on the grade of VUR. A meta-analysis of 5527 children showed that only 72% of grade III VUR and 63% of grade IV VUR was cured by injection.59 The efficacy of re-infection rates and renal scarring has been compared in open anti-reflux surgery versus antimicrobial prophylaxis in three old studies.60–63 None of these studies found any benefit of surgery over prophylactic antibiotic treatment. A recent Cochrane review64 compared injection of a bulking agent with prophylactic antibiotics. The injection was not superior to prophylactic antibiotics in preventing recurrent UTIs and renal scarring, or a wait-and-see approach. www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. 1663 Review A 100 Percentage of children with reflux 80 60 40 20 Grade I Grade II Grade IV (bilateral) Grade IV (unilateral) 0 B 100 Percentage of children with reflux 80 60 40 Bilateral age (6–10 years) Bilateral age (3–5 years) Unilateral age (6–10 years) Unilateral age (3–5 years) Bilateral age (1–2 years) Unilateral age (1–2 years) 20 0 0 1 2 3 4 5 Years since presentation Figure 4: Probability of vesicoureteral reflux resolution over time (A) Percentage of children with reflux over time according to vesicoureteral reflux grade. (B) Percentage of children with reflux over time according to age.55 Reproduced from Elder et al.56 Preventive treatments 1664 infections compared with children given placebo. The Cochrane report64 included these three studies in a separate analysis of low-bias studies. This report did not find any significant reduction in the number of repeat UTIs between the actively treated group and the placebo group. A recent analysis of cost-effectiveness68 used individual patient data from the RIVUR study and concluded that treatment of children with low-grade VUR (ie, grades I–III) was not cost effective. In the RIVUR and PRIVENT studies that suggested benefits from antimicrobial prophylaxis, the number of children that had to be treated to prevent a child from getting breakthrough UTIs was high. In the RIVUR study, long-term antimicrobial prophylaxis reduced recurrence of UTIs from 27·4% to 14·8% during a 2-year follow-up period, which means that approximately eight children with VUR need to be treated for one child to benefit. The Swedish reflux trial focused on a high-risk group of children aged between 1 and 2 years with high-grade (III and IV) VUR. This small study showed completely different results in boys and girls. The trial found a statistically significant reduction in infections only in girls,69 whereas in boys the number of recurrent infections remained low even in the control group. There was a total of seven re-infections among all boys and only one re-infection in the 26 surveyed boys during a 2-year follow-up.70 The Swedish reflux trial did also find that in girls randomly assigned to different antibiotics, renal scarring occurred significantly less frequently compared with the control group.71 In our expert opinion, young children with high grade VUR are likely to benefit from antibiotic prophylaxis and a trial using antimicrobial prophylaxis in children with several recurrent episodes of acute pyelonephritis is warranted. A major side-effect of using prophylactic antibiotics long term is the development of antimicrobial resistance both in the faecal flora and the bacteria causing the recurrent UTI.67,72 The Cochrane review64 showed significantly increased antibiotic resistance to the drug used on the basis of six studies. Prophylactic antibiotics Other prophylactic measures The aim of prophylactic antibiotics is to reduce the number of recurrent episodes of acute pyelonephritis and to reduce renal scarring. A recent Cochrane review64 included nine studies that compared antibiotic treatment to a placebo, or no treatment at all. These studies did not show any statistically significant benefit from using prophylaxis to prevent recurrent UTIs or to prevent new uptake defects seen on DMSA scans. Three well-conducted studies—PRIVENT,65 RIVUR,66 and the study by Hari and others67—showed surprisingly opposing results to each other. RIVUR and PRIVENT reported fewer infections in children receiving prophylactic antibiotics, whereas the study by Hari and others showed that children receiving prophylactic cotrimoxazole had a 3-times higher chance of recurrent A meta-analysis of randomised controlled trials by Jepson and colleagues73 found that cranberry-based products do not reduce recurrent UTIs compared with placebo, and that excessive intake of juice might contribute to dental cavities, diarrhoea, and obesity. Probiotics have also not been shown to reduce recurrent UTIs in randomised trials of children.74 Circumcision soon after birth has been shown to reduce the chance of getting an episode of acute pyelonephritis by 90% in healthy boys.75,76 However, the number of children needed to be circumcised to protect one case of acute pyelonephritis is too high (number needed to treat is 111) to warrant routine use. Unreliable data also support circumcision in children with major urinary malformations who need general anaesthesia for other urological reasons. www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. Review Bladder and bowel dysfunction Bladder and bowel dysfunction is an abnormal pattern of faecal elimination characterised by bowel and blad­der incontinence, and withholding faeces or urine in previously toilet-trained children who have no under­ lying anatomical or neurological abnormalities. Bladder and bowel dysfunction is present in approximately 30–50% of children with a first UTI.77,78 Screening for bladder and bowel dysfunction can be done by a general practitioner using a short nine-item questionnaire79 or by asking about symptoms of constipation and daytime voiding abnormalities. The sensitivity of this ques­ tionnaire ranges from 81% to 93% and its specificity ranges from 87% to 91%. Treatment of bladder and bowel dysfunction, consists of pharmacological treat­ ment of consti­ pation (if present) and behavioural treatment of bladder dysfunction (eg, timed voiding). No large trial has looked at the effectiveness of various treatment options in reducing recurrent UTIs; however, retrospective studies suggest that treatment might reduce symp­toms.80–82 Bladder and bowel dysfunction tends to spontaneously resolve over time.83 Children who have both VUR and bladder and bowel dysfunction seem to have a much higher chance of recurrent UTIs than do children with only bladder and bowel dysfunction, only VUR, or neither.84 Whether treatment of bladder and bowel dysfunction precludes or reduces the need to screen children for VUR has not been studied. Radiological investigations The most important rationale for routine imaging in young children with a UTI is to identify anatomical abnormalities of the genitourinary tract that require evaluation or management. Imaging can provide infor­ mation on VUR, obstructed urine flow, and the relative function of kidneys. Ultrasonography Information provided by a renal and bladder ultrasound is dependent on the investigator, but it does give an anatomical picture of the kidneys including kidney size. A renal and bladder ultrasound can also provide information on dilatation of the renal pelvis or ureter, on bladder emptying, and on the thickness of the bladder wall. Notably, the accuracy of a renal and bladder ultrasound for the detection of high-grade VUR is suboptimal.84 Most abnormalities detected by ultrasound are minor anatomical variants that do not require correction.84 This technique is estimated to yield abnormalities that need further management (ie, requiring additional evaluation or surgery) in only 1–2% of cases of first febrile UTI in children aged 2–24 months.7 Given these test characteristics we question whether routine use of ultrasound, even if non-invasive, is justified after the first febrile UTI. To our knowledge no studies on cost-effectiveness have examined this issue. Currently the AAP recommends routine ultrasonography in children younger than 2 years with a febrile UTI and in the UK in babies younger than 6 months.6,7 A renal ultrasound has the benefit of identifying all children with major renal malformations and we recommend it to be done after the first UTI in all children younger than 2 years. The AAP also recommends that a renal and bladder ultrasound should be done after the acute symptoms of a UTI have resolved to reduce the risk of false-positive results secondary to renal inflammation during the acute episode.7 A renal and bladder ultrasound can also be used in the acute phase in children in which the fever persists for more than 72 h despite appropriate antibiotic treatment to help to identify major malformations and complications of the infection (eg, renal or perirenal abscess, pyonephrosis). Micturating cystourethrogram After catheterisation the bladder is filled with radiopaque contrast material and radiographs are obtained while the child voids. The procedure lasts approximately 30 min and, in girls, results in some radiation to the gonads. The AAP guideline recommends postponing a micturating cystourethrogram until the second febrile UTI occurs in children aged 2–24 months, unless the renal and bladder ultrasound is abnormal.7 National Institute for Health and Care Excellence (NICE) guidelines recommend a micturating cystourethrogram for infants up to the age of 3 years with their first atypical UTI (eg, sepsis, infection with an organism other than E coli, and failure to respond to antibiotics within 48 h) or in infants with recurrent UTIs.6 Renal scintigraphy Renal scintigraphy using DMSA can detect acute pyelonephritis and renal scarring in the early (within 2 weeks of a UTI) and late (≥ 4 months after a UTI) stages (figure 2). DMSA is injected intravenously and Panel: Suggestions for important research topics in UTI • Improving accuracy in diagnosing a UTI: • Can the absence of leucocyturia be used to rule out a UTI? • Are UTIs with low bacterial counts true UTIs? • Can biomarkers differentiate between a true UTI and contamination? • Is there a role for urinary or blood biomarkers in defining the location of a UTI? • Further defining the prevalence of VUR in healthy infants • Is there a role for prophylactic antibiotics or circumcision in children with severe urinary tract malformations? • Can anti-inflammatory treatment during an acute episode of febrile UTI reduce renal scarring later? • Further defining the role of antimicrobial prophylaxis and injection of a bulking agent in children with VUR • Can treatment of bladder and bowel dysfunction reduce the number of recurrent UTIs? • Further studies of decade-long outcomes in children with post-infectious renal scars UTI=urinary tract infection. VUR=vesicoureteral reflux. www.thelancet.com Vol 395 May 23, 2020 Téléchargé pour cdsm cdsm ([email protected]) à Central Military Hospital à partir de ClinicalKey.fr par Elsevier sur novembre 09, 2022. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée. Copyright ©2022. Elsevier Inc. Tous droits réservés. 1665 Review a decreased uptake of DMSA represents pyelonephritis or scarring. However, DMSA scans are expensive, invasive, and expose children to radiation. Scintigraphy at the time of an acute UTI (early DMSA) provides information about the extent of renal parenchymal involvement. Many children with highgrade VUR have renal involvement; therefore, a DMSA scan can be done soon after a UTI is detected. This observation has prompted some experts to suggest that early DMSA can be used as an initial imaging method to identify children at higher risk for VUR (the top-down approach).85 However, since most young febrile children with a UTI have pyelonephritis and a positive early DMSA, this strategy could lead to identification of a large number of children who might be at risk of a future UTI or renal scarring.86 Neither AAP7 nor NICE6 guidelines recommend using an early DMSA scan in the routine evaluation of children with their first UTI. A late DMSA scan (4–12 months after acute infection) to detect renal scars is recommended by NICE guidelines for children younger than 3 years with atypical or recurrent UTIs and for children older than 3 years with recurrent UTIs. The AAP guidelines do not recommend routine use of late DMSA scans. We recommend a follow-up with a DMSA in children with a high chance of major kidney scarring—ie, children with high-grade VUR and several recurrences of febrile UTIs—especially if the results would be useful in preventing further invasive procedures (eg, some urologists use DMSA to limit the number of children with VUR and breakthrough febrile UTIs with ureteral reimplantation). Conclusion The management of children who have had a UTI has developed markedly over the past decade. The focus has shifted to a stronger emphasis on making an accurate diagnosis, and present guidelines from many parts of the world recommend less routine imaging in children after their first uncomplicated UTI. There is also an international debate on the usefulness of an ultrasound in all children below the age of 2 years with a UTI, or whether the ultrasound should be done in only a selected group of children. The importance of VUR has been down-played whereas other factors have been emphasised. Bacterial virulence is recognised as an important factor in single episodes of febrile UTIs. Bladder and bowel dysfunction is increasingly acknowledged to be of high importance in recurrent UTIs and asymptomatic bacteriuria. Controversially, many children in several countries still routinely have surgery for VUR. We highlighted some important areas for further research in the panel. Contributors Both authors wrote the first draft, revised, and approved the final manuscript. Declaration of interests We declare no competing interests. 1666 References 1 Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U. Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991; 66: 232–34. Winberg J, Andersen HJ, Bergström T, Jacobsson B, Larson H, 2 Lincoln K. Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand Suppl 1974; 63: 1–20. 3 Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. 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