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How common is co-existing meningitis in infants with urinary tract infection?

Three Part Question

In [an infant with UTI] is [a lumbar puncture] indicated to [rule out co-existing bacterial meningitis]?

Clinical Scenario

You are asked to review a febrile 2-month-old infant who presented to the accident and emergency department. The urine analysis carried out before your arrival is suggestive of urinary tract infection (UTI) (urine dipstick: positive for nitrites and white blood cells (WBCs); microscopy: 220 WBCs per high powered field). On examination the infant appears well and has no signs suggestive of meningitis. However, you recall a senior colleague stating that young infants with UTI should always have a full septic workup to rule out co-existing bacterial meningitis. You wonder if there is any evidence to support routinely performing a lumbar puncture in this setting?

Search Strategy

Medline was searched using the PubMed interface (1950葉o date/no limits set)
Search of the ISI Web of Science (1900葉o date)EMBASE (1980葉o date) and Scopus (1900葉o date)(4th Jan 2011)
Cochrane Library
Medline:(1) a keyword search using (Urinary Tract Infection OR pyelonephritis OR cystitis) AND (meningitis OR meningoencephalitis OR lumbar puncture) AND (neonat* OR infant) retrieved 507 publications, of which 11 were relevant,and (2) a search using the MeSH terms (選nfant, Newborn OR 選nfant) AND 繕rinary Tract Infections AND 舛entral Nervous System Infections retrieved 172 publications, but no further relevant papers were identified.
Embase/Scopus:using the same keyword strategy as above yielded 106, 328 and 163 matches, respectively, among which 3 further relevant paper(s) were identified.
Cochrane:繕rinary Tract Infection and 叢yelonephritis retrieved 18 Cochrane reviews, none of which were relevant.

Search Outcome

Publications that described a group of fewer than 30 infants with UTI and those providing insufficient detail were excluded. All relevant publications were hand-searched for additional references, which identified a further two reports (Goldman, Bergstrm).

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Schnadower et al,
2010,
1609 infants aged 12 months with UTI who underwent LP (UTI definition: positive urine culture with ≥1000 CFU/ml for SPA specimen; ≥50 000 CFU/ml for catheter specimen; ≥10 000 CFU/ml for catheter specimen if associated with positive urine analysis)Retrospective cohort study (level 2b)Culture-proven meningitis, probable bacterial meningitis and aseptic meningitisBacterial meningitis: 2 (0.1%) (Escherichia coli: 2) Probable bacterial meningitis: 3 (0.2%) Aseptic meningitis: 295 Part of a larger study population of infants with UTI (n=1895)
Yam et al,
2009,
106 infants aged 06 months with UTI who underwent LP (UTI definition: any pure growth for SPA specimen and catheter specimen; ≥108 CFU/ml for clean catch) Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 0 Aseptic meningitis: 12The study only included infants who had urine and CSF cultures obtained on the same day. The number of infants with UTI who did not undergo LP is not provided None of the patients had received antibiotics prior to urine and CSF specimens being obtained (based on history and testing of urine antimicrobial activity)
Bonsu et al,
2007
258 infants aged 03 months with UTI who underwent LP (UTI definition: positive urine culture with ≥1000 CFU/ml for SPA specimen; ≥10 000 CFU/ml for catheter specimen; ≥100 000 CFU/ml for clean catch)Retrospective cohort study (level 2b)Culture-proven meningitisBacterial meningitis: 1 (0.4%) (E coli) Part of a larger study population of febrile infants who had a full septic workup (n=3765)
Vuillermin et al,
2007
75 infants aged 03 months with UTI who underwent LP (UTI definition: any pure growth on SPA specimen; positive urine culture with ≥100 000 CFU/ml for catheter specimen; ≥108 CFU/ml for clean catch) Retrospective cohort study (level 2b)Culture-proven meningitis, probable bacterial meningitis and aseptic meningitisBacterial meningitis: 0 Probable bacterial meningitis (culture-negative): 1 (1.3%) (95% CI 0.003% to 7.2%) Aseptic meningitis: 5 Part of a larger study population of infants with UTI (n=161) Study included one infant with scanty growth of E coli and Enterococcus faecalis in CSF, interpreted as a contaminated sample by the authors (CSF: 8 WBC/ml) Three patients with aseptic meningitis had received antibiotics prior to LP (ie, cultures potentially false-negative); however, one of these cases was positive for enterovirus on PCR
Dayan et al,
2004
125 infants aged 02 months with UTI who underwent LP (UTI definition: any pure growth on SPA specimen; positive urine culture with ≥10 000 CFU/ml for catheter specimen)Retrospective cohort study (level 2b)Culture-proven meningitisBacterial meningitis: 1 (0.8%) (E coli)Part of a larger study population of infants with UTI (n=131) Upper limit of 95% CI for co-existing bacterial meningitis 3.7% (lower limit not provided)
Adler-Shohet et al,
2003,
260 infants aged 06 months with UTI who underwent LP (UTI definition: positive urine culture with ≥10 000 CFU/ml for catheter specimen; ≥100 000 CFU/ml for bag specimen)Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 1 (0.4%) (E coli) Aseptic meningitis: 31 Part of a larger study population of infants with UTI (n=386) The group of infants with aseptic meningitis included one case of suspected bacterial meningitis (based on strongly suggestive CSF results)
Finkelstein et al,
2001,
215 infants aged 02 months with UTI who underwent LP (no UTI definition provided)Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 0 Aseptic meningitis: 11Part of a larger study population of febrile infants who had a full septic workup (n=1629)
Syrogiannopoulos et al,
2001
117 infants aged 03 months with UTI who underwent LP (no UTI definition provided)Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 0 Aseptic meningitis: 15Part of a larger study population of infants with UTI (n=206)
Bachur and Caputo,
1995,
244 children aged 024 months with UTI who underwent LP (UTI definition: positive urine culture with ≥1000 CFU/ml for SPA specimen; ≥10 000 CFU/ml for catheter specimen)Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 3 (1.2%) (E coli: 3) Aseptic meningitis: 12 Fewer than 10% of the children in this cohort were aged between 12 and 24 months (exact figure unclear) The group of infants with aseptic meningitis included one case with CSF results suggestive of bacterial meningitis in whom the CSF sample was 僧ishandled according to the authors (ie, potentially false-negative culture)
Wang et al,
1994
51 infants aged 02 months with UTI who underwent LP (UTI definition: positive urine culture with ≥100 000 CFU/ml for SPA or catheter specimen)Retrospective cohort study (level 2b)Culture-proven meningitisBacterial meningitis: 1 (2.0%) (E coli and enterococci)Part of a larger study population of infants with UTI (n=95) Mixed growth of enteric pathogens in CSF culture indicates potential contamination of the sample
Magin et al,,
2007
75 infants aged 01 months with UTI who underwent LP (UTI definition: positive urine culture with ≥10 000 CFU/ml for catheter specimen)Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 0 Aseptic meningitis: 12Part of a larger study population of neonates with UTI (n=172)
Shah et al,
2008
82 infants aged 02 months with UTI who underwent LP (UTI definition: positive urine culture with ≥1000 CFU/ml for SPA specimen; ≥50 000 CFU/ml for catheter specimen; ≥10 000 CFU/ml for catheter specimen in association with positive urine analysis)Prospective cohort study (level 1b)Culture-proven and aseptic meningitisBacterial meningitis: 1 (1.2%) (Enterobacter species)Aseptic meningitis: up to 15 (depending on definition used)Part of a larger study population of infants with UTI (n=91), who were part of a larger study of febrile infants (n=1025) A large proportion (60%) of infants with sterile CSF pleocytosis had a traumatic LP, complicating interpretation of the data
Ginsburg and McCracken Jr
1982,
88 infants aged 08 months with UTI who underwent LP (no UTI definition provided; all patients had SPA and urine cultures with ≥40 000 CFU/ml)Retrospective cohort study (level 2b)Culture-proven meningitisBacterial meningitis: 0Part of a larger study population of infants with UTI (n=100)
Goldman et al,
2005,
143 infants aged 03 months with pyuria and fever who underwent LP (pyuria definition: ≥10 WBC/mm3 )Retrospective cohort study (level 2b)Culture-proven meningitisBacterial meningitis: 0*Part of a larger study population of infants with pyuria (n=217); 81% of presumed UTI were later confirmed by culture *The CSF cultures of three patients grew Staphylococcus epidermidis. Two were interpreted as contaminants; in one patient with a VP shunt, E coli were simultaneously isolated from the urine (ie, likely coincidental finding)
Bergstrm et al,
1972
31 infants aged 01 months with UTI who underwent LP (UTI definition: positive urine culture with ≥100 000 CFU/ml for bag specimen and urine WBC count ≥25/mm3 in males and ≥50/mm3 in females) Retrospective cohort study (level 2b)Culture-proven and aseptic meningitisBacterial meningitis: 6 (19.4%) (organisms not reported) Aseptic meningitis: 12Part of a larger study population of neonates with UTI (n=80) Study is likely to have overestimated the risk of co-existing meningitis considerably (see commentary)

Comment(s)

UTIs are common. Between 1% and 15% of young children presenting with fever in the outpatient setting have an underlying UTI (Bergstrm, Hoberman). In comparison to older children, UTI in infants is more commonly associated with bacteraemia, occurring in 412% of cases (Bergstrm, Dayan, Bonsu, Adler-Shohet, Wang, Magin). It has been postulated that infants with UTI are therefore at higher risk of co-existing meningitis as a result of bacterial dissemination to the central nervous system (CNS).

The detection of co-existing meningitis in children with UTI is important, as the treatment of the former differs considerably from that of UTI alone. UTI may be treated with oral antibiotics or antibiotics that have poor cerebrospinal fluid (CSF) penetration, and the treatment duration is generally shorter. Consequently, failure to detect co-existing meningitis may result in inadequate or partial treatment of the CNS infection. Although performing a lumbar puncture in all infants with UTI is arguably the safest strategy, this is a procedure associated with pain and potential complications. The latest National Institute for Health and Clinical Excellence clinical guideline on UTI in children (CG54) recommends starting children older than 3 months of age with 爽ncomplicated UTI on oral antibiotics, such as a cephalosporin or co-amoxiclav. For children younger than 3 months, the reader is referred to the guideline on feverish illness in children (CG47). However, this guideline does not specifically indicate whether infants under the age of 3 months with confirmed, uncomplicated UTI should routinely undergo lumbar puncture to rule out co-existing meningitis.

Fourteen reports identified in our literature search were retrospective studies; only one study was prospective (Shah). The majority of studies included only infants under 3 months of age. In all but one study,(Goldman) UTI was defined as a positive urine culture; however, different microbiological cut-offs were used to define culture positivity. Also, different methods of urine collection, including urine bag, clean catch, catheterisation and suprapubic aspirate, were used. This is important, as particularly the first two methods are prone to contamination, which may result in false-positive urine culture results. Therefore, there is the possibility that some patients with meningitis included in these studies were falsely classified as having co-existing UTI.

The frequently quoted study by Bergstrm et al found that six (19.4%) of 31 neonates with UTI had co-existing bacterial meningitis. This study has previously been criticised as likely to considerably overestimate the risk of co-existing bacterial meningitis as all specimens were obtained using urine bags, which may have resulted in a considerable overestimate of co-existing UTI (Goldman, Vuillermin). Only one study based the diagnosis of UTI on dipstick analysis, therefore being the only study that is directly applicable to our clinical scenario. Importantly, this study reflects 喪eal life practice, as culture results are not available at the time of the initial presentation and consequently can not be used to make decisions about further investigations, including lumbar puncture, and subsequent treatment.

The frequently quoted study by Bergstrm et al15 found that six (19.4%) of 31 neonates with UTI had co-existing bacterial meningitis. This study has previously been criticised as likely to considerably overestimate the risk of co-existing bacterial meningitis as all specimens were obtained using urine bags, which may have resulted in a considerable overestimate of co-existing UTI.4 14 Also, fewer than half of the infants with UTI included in this report underwent lumbar puncture. Consequently, as infants with meningitis (ie, those appearing sicker) would have been more likely to be subjected to a lumbar puncture, this is likely to have skewed the estimate of co-existing meningitis even further. This important limitation also applies to some other studies included in this review in which a considerable proportion of participants did not undergo lumbar puncture.

In the remaining 14 studies included in this review, the rate of co-existing bacterial meningitis in infants with UTI ranged from 0% (six studies)Yam, Finklestein, Syrogiannopoulos, Magin, Ginsburg Bergstrm to 2.0% (one study)Wang. Notably, the latter study was relatively small and included only a single patient with co-existing meningitis. The heterogeneity of the 15 studies, particularly with respect to age of participants, urine.Although the available data have considerable limitations, they suggest that in infants under the age of 3 months with UTI, the 奏rue rate of co-existing bacterial meningitis is likely to be under 1%. Whether this level of risk is sufficient to justify universal lumbar puncture is debatable. There are currently insufficient data on this issue in infants aged between 3 and 12 months. Further data from large, well-designed studies are needed to establish more precisely the risk of meningitis in infants with UTI in this age group and consequently the role of lumbar puncture

Editor Comment

The proportion of infants with urinary tract infection who had co-existing meningitis (culture-proven and probable cases combined) in the studies included in this review. Plot and confidence intervals can be found at http://adc.bmj.com/content/96/6/602.2.full (ADC registration required)

CFU, colony forming units; CSF, cerebrospinal fluid; LP, lumbar puncture; SPA, suprapubic aspirate; UTI, urinary tract infection; VP, ventriculo-peritoneal; WBC, white blood cell.

Clinical Bottom Line

Between 0% and 2% of infants under the age of 3 months with urinary tract infection have co-existing bacterial meningitis. (Grade B)

There are insufficient data on the rate of co-existing bacterial meningitis in older infants (aged 312 months). (Grade D)

References

  1. Schnadower D, Kuppermann N, Macias CG, et al . Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics 2010;126:107483.
  2. Yam AO, Andresen D, Kesson AM, et al . Incidence of sterile cerebrospinal fluid pleocytosis in infants with urinary tract infection. J Paediatr Child Health 2009;45:3647.
  3. Bonsu BK, Harper MB . Leukocyte counts in urine reflect the risk of concomitant sepsis in bacteriuric infants: a retrospective cohort study. BMC Pediatr 2007;7:24.
  4. Vuillermin PJ, Starr M . Investigation of the rate of meningitis in association with urinary tract infection in infants 90 days of age or younger. Emerg Med Australas 2007;19:4649.
  5. Dayan PS, Hanson E, Bennett JE, et al . Clinical course of urinary tract infections in infants younger than 60 days of age. Pediatr Emerg Care 2004;20:858.
  6. Adler-Shohet FC, Cheung MM, Hill M, et al . Aseptic meningitis in infants younger than six months of age hospitalized with urinary tract infections. Pediatr Infect Dis J 2003;22:103942.
  7. Finkelstein Y, Mosseri R, Garty BZ . Concomitant aseptic meningitis and bacterial urinary tract infection in young febrile infants. Pediatr Infect Dis J 2001;20:6302.
  8. Syrogiannopoulos GA, Grivea IN, Anastassiou ED, et al . Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infection. Pediatr Infect Dis J 2001;20:92730.
  9. Bachur R, Caputo GL . Bacteremia and meningitis among infants with urinary tract infections. Pediatr Emerg Care 1995;11:2804.
  10. Wang SF, Huang FY, Chiu NC, et al . Urinary tract infection in infants less than 2 months of age. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1994;35:294300.
  11. Magn EC, Garca-Garca JJ, Sert SZ, et al . Efficacy of short-term intravenous antibiotic in neonates with urinary tract infection. Pediatr Emerg Care 2007;23:836.
  12. Shah SS, Zorc JJ, Levine DA, et al . Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infections. J Pediatr 2008;153:2902.
  13. Ginsburg CM, McCracken GH Jr. . Urinary tract infections in young infants. Pediatrics 1982;69:40912.
  14. Goldman RD, Matlow A, Linett L, et al . What is the risk of bacterial meningitis in infants who present to the emergency department with fever and pyuria? CJEM 2003;5:3949.
  15. Bergstrm T, Larson H, Lincoln K, et al . Studies of urinary tract infections in infancy and childhood. XII. Eighty consecutive patients with neonatal infection. J Pediatr 1972;80:85866.
  16. Hoberman A, Wald ER, Reynolds EA, et al . Is urine culture necessary to rule out urinary tract infection in young febrile children? Pediatr Infect Dis J 1996;15:3049.
  17. Lin DS, Huang SH, Lin CC, et al . Urinary tract infection in febrile infants younger than eight weeks of Age. Pediatrics 2000;105:E20
  18. National Institute for Health and Clinical Excellence. Clinical Guideline: Urinary Tract Infection in Children Diagnosis, Treatment and Long-Term Management (CG54) 2004 http://www.nice.org.uk/nicemedia/pdf/CG54fullguideline.pdf (accessed 4 Jan 2011).
  19. National Institute for Health and Clinical Excellence. Clinical Guideline: Feverish Illness in Children Assessment and Initial Management in Children Younger Than 5 Years of Age (CG47). 2007 http://www.nice.org.uk/nicemedia/pdf/CG47Guidance.pdf (accessed 4 Jan 2011).