Urinary tract infection in children: recurrent infections

Abstract

Introduction

Up to 11% of girls and 7% of boys will have had a urinary tract infection (UTI) by the age of 16 years, and recurrence of infection is common. Vesicoureteric reflux (VUR) is identified in up to 40% of children being investigated for a first UTI, and is a risk factor for, but weak predictor of, renal parenchymal defects.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylactic antibiotics to prevent recurrent urinary tract infection in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2013 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).

Results

We found three studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following intervention: prophylactic antibiotics.

Key Points

Up to 11% of girls and 7% of boys will have had a UTI by the age of 16 years. Recurrent UTI is common

Vesicoureteric reflux (VUR) is identified in up to 40% of children being investigated for a first UTI, and it is a risk factor for, but weak predictor of, renal scarring.

Renal parenchymal defects occur in 5% to 15% of children within 1 to 2 years of their first presentation with UTI, and it is associated with increased risks of progressive renal damage. The risk of parenchymal defects probably diminishes over time.

Prophylactic antibiotics may be more effective than placebo at reducing the risk of recurrent UTI; however, they may increase microbial resistance to the prophylactic drug.

• Recent, well-conducted RCTs suggest a limited benefit of prophylaxis.

Prophylactic antibiotics may be more effective than placebo at reducing renal parenchymal scarring in children with VUR.

We found no systematic review or RCT evidence comparing different durations of antibiotics.

Nitrofurantoin appears to be more effective than other prophylactic antibiotics, but this is balanced by the increased risk of side-effects and treatment drop-out.

Clinical context

General background

Prophylactic antibiotics are likely to reduce symptomatic UTI in all children and renal parenchymal defects in children with vesicoureteric reflux (VUR). However, the effect is small, the ideal duration of treatment unclear, and the possibility of differential benefit among sub-cohorts of children not investigated. Of the suitable antibiotics, nitrofurantoin causes the least microbial resistance, but the most side-effects.

Focus of the review

This systematic overview concentrates on the use of prophylactic antibiotics to prevent UTI and renal parenchymal defects in children with or without vesicoureteric reflux (VUR). This has been an area of professional debate. New evidence has emerged since our last review, modifying the conclusions of previous BMJ Clinical Evidence summaries.

Comments on evidence

Two updated systematic reviews have significantly added to our knowledge since our last review. They include several recently published studies, and one of these is especially large and of high quality. These have led to a subtle change in the evidence.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, July 2009, to December 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 284 studies. After deduplication and removal of conference abstracts, 175 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 142 studies and the further review of 33 full publications. Of the 33 full articles evaluated, two systematic reviews and one RCT were included at this update.

About this condition

Definition

The presence of a pure growth of at least 10⁷ colony-forming units of bacteria per litre of urine indicates a diagnosis of urinary tract infection (UTI). Lower counts of bacteria may be clinically important, especially in boys, and in specimens obtained by urinary catheter. Any growth of typical urinary pathogens is considered clinically important if obtained by suprapubic aspiration. Different presentation and differential risk have often led to the stratification of children by age for clinical management and research. NICE guidance defines three age groups: under 3 months; 3 months to 3 years; and over 3 years. Other publications have defined risk groups as children aged up to 1 year, up to 7 years, and up to 12–16 years. Recurrent UTI is defined as a further infection by a new organism. Relapsing UTI is defined as a further infection with the same organism.

Incidence/ Prevalence

Boys are more susceptible to UTI than girls before the age of 6 months; thereafter, the incidence is substantially higher in girls than in boys. Estimates of the true incidence of UTI depend on rates of diagnosis and investigation. Observational studies have found that UTIs have been diagnosed in Sweden in at least 2% of boys and girls by the age of 2 years, in 8% of girls and 2% of boys by age 7 years, and in the UK in 11% of girls and 7% of boys by age 16 years.

Aetiology/ Risk factors

The normal urinary tract is sterile. Contamination by bowel flora may result in urinary infection if a virulent organism is involved. In neonates, infection may originate from other sources. Escherichia coli accounts for about 75% of all pathogens. Proteus is more common in boys (one study found that proteus caused 33% of UTI infections in boys aged 1–16 years, compared with 0% of UTI infections in girls of the same age). In a study of children presenting with acute pyelonephritis, UTIs caused by non-E coli organisms were more likely to be associated with permanent renal damage than E coli (83% v 57%). Obstructive anomalies are found in up to 4%, and vesicoureteric reflux (VUR) in 8% to 40% of children being investigated for their first UTI. One meta-analysis of 12 cohort studies (537 children admitted to hospital for UTI, 1062 kidneys) found that 36% of all kidneys had parenchymal defects on dimercaptosuccinic acid (DMSA) scintigraphy, and that 59% of children with VUR on micturating cystourethrography had at least one scarred kidney (pooled positive likelihood ratio 1.96, 95% CI 1.51 to 2.54; pooled negative likelihood ratio 0.71, 95% CI 0.58 to 0.85). There was evidence of heterogeneity in likelihood ratios among studies. The authors concluded that VUR is a weak predictor of renal damage in children admitted to hospital. Thus, although VUR is a major risk factor for adverse outcome, other factors, some of which have not yet been identified, are also important. Family history VUR itself runs in families. The mode of inheritance is autosomal dominance with variable penetrance and expressivity. In one review, the incidence of reflux in siblings ranged from 26% (a cohort of asymptomatic siblings) to 86% (siblings with a history of UTI). In another review, 32% of siblings had VUR, but only 2% was of a severe grade (Grade III and above). The rate in the general population has been calculated at 1% to 3%. Although some gene variants seem more common in children who suffer renal damage, no clear link has yet been established between specific genes and an adverse outcome. Local or systemic immune problems are also likely to be factors in the development of UTI.

Prognosis

Recurrence A UK study found that 78% of girls and 71% of boys presenting with UTI within the first year of life experienced recurrence, and that 45% of girls and 39% of boys presenting after their first year of life developed further infections. VUR In a longitudinal study, 84% of children (572 children with UTI and VUR) had spontaneous resolution during medical follow-up at between 5 and 15 years. Renal parenchymal defects A systematic review of imaging in childhood UTI suggested that renal parenchymal defects (assessed with intravenous pyelogram [IVP] or DMSA scan) occurs in 5% to 15% of children within 1 to 2 years of their first diagnosed UTI. Between 32% and 70% of these parenchymal defects were noted at the time of initial assessment, suggesting a high level of pre-existing scarring, perhaps caused by previously unrecognised infection. This percentage did not substantially alter, despite an increasing referral rate, during the 3 years studied. A retrospective population-based study in the UK suggested that 4.3% of boys and 4.7% of girls develop parenchymal defects (2842 children assessed using DMSA scans after their first referral for UTI). New or progressive renal parenchymal defects and recurrent UTI The systematic review reported on four studies that provided at least 2 years' follow-up: new renal parenchymal defects developed in 2% to 23% of children, and existing renal parenchymal defects progressed in 6% to 34%. It is unclear whether figures for new parenchymal defects included any children who were previously unscarred. The highest rates of renal parenchymal defects were associated with the highest rates of recurrent UTI. A further study showed that, in children aged 5 years or older, abnormal DMSA scans were noted in 64/118 (55%) children presenting with recurrent UTI, whereas 7/44 (15%) who presented with 'first UTI' had renal parenchymal defects (OR for recurrences causing renal parenchymal defects 6.3, 95% CI 2.6 to 15.2). However, recurrent UTI may be less important as a risk factor for renal parenchymal defects in older children. One study showed that, in children with initially normal scans at 3 or 4 years of age, 5/176 (3%) children aged 3 years at presentation, and 0/179 (0%) aged 4 years at presentation, had developed renal parenchymal defects between 2 and 11 years later. Of those children who developed renal parenchymal defects, 4/5 (80%) had a definite history of recurrent UTI, in all cases at least three episodes (OR for recurrences causing renal parenchymal defects 11.5, 95% CI 1.3 to 106.1). Another study (287 children with severe VUR treated either medically or surgically for any UTI) used serial DMSA scintigraphy to evaluate the risk of renal parenchymal defects over 5 years. It found that younger children (aged <2 years) were at greater risk of renal parenchymal defects than older children, regardless of treatment for the infection (deterioration in DMSA scan >5 years: 21/86 (24%) for younger children v 27/201 (13%) for older children; RR 1.82, 95% CI 1.09 to 3.03). It is likely that children who present when older, and who are found to have renal parenchymal defects, will have had at least one previous UTI that remained undiagnosed. Many children seem to lose their susceptibility to renal damage with age. Consequences for longer term One long-term follow-up study in the UK found that children with renal parenchymal defects and vesicoureteric reflux at presentation, or with just one of these followed by documented UTI, were associated with an increased risk of progressive renal damage compared with children presenting without these features (RR of progressive renal damage 17, 95% CI 2.5 to 118). Persistent renal parenchymal defects may be associated with future complications, such as poor renal growth, recurrent adult pyelonephritis, impaired glomerular function, early hypertension, and end-stage renal failure. A combination of recurrent UTI, severe vesicoureteric reflux, and the presence of renal parenchymal defects at first presentation is associated with the worst prognosis.

Aims of intervention

To prevent recurrence, renal damage, and long-term complications.

Outcomes

Recurrent infection; renal parenchymal defects; and adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal December 2013. Databases used to identify studies for this systematic review included: Medline 1966 to December 2013, Embase 1980 to December 2013, The Cochrane Database of Systematic Reviews 2013, issue 11 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as 'open', 'open label', or not blinded, unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see Table 2 ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.bmj.com).

Table 1.

GRADE evaluation of interventions for UTI in children

Important outcomes	Cure of infection, recurrent infection, renal parenchymal defects, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of prophylactic antibiotics to prevent recurrent urinary tract infection in children?
at least 10 RCTs (at least 1069)	Recurrent infection	Prophylactic antibiotics v placebo/no treatment	4	0	–1	0	0	Moderate	Consistency point deducted for different results depending on analysis
3 (446)	Renal parenchymal defects	Prophylactic antibiotics v placebo/no treatment	4	–1	0	–1	0	Low	Quality point deducted for lack of blinding in two studies; directness point deducted for different durations of antibiotic prophylaxis

Type of evidence: 4 = RCT; 2 = Observational; Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.

Glossary

Dimercaptosuccinic acid (DMSA) scintigraphy

A scan following intravenous injection of a radioisotope solution, which is excreted by the kidneys. The scan yields information about the structure and function of the urinary tract.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Pyelonephritis

Inflammation of the kidney and its pelvis caused by bacterial infection.

Disclaimer

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