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. Author manuscript; available in PMC: 2014 Sep 1.
Published in final edited form as: Pediatr Infect Dis J. 2013 Sep;32(9):1024–1026. doi: 10.1097/INF.0b013e31829063cd

Cerebrospinal Fluid Pleocytosis in Febrile Infants 1-90 Days with Urinary Tract Infection

Elizabeth H Doby 1, Chris Stockmann 1, E Kent Korgenski 1,2, Anne J Blaschke 1, Carrie L Byington 1
PMCID: PMC3755104  NIHMSID: NIHMS464869  PMID: 23584580

INTRODUCTION

Urinary tract infection (UTI) is the most commonly diagnosed serious bacterial infection (SBI) in febrile infants evaluated in the first 90 days. In these infants, lumbar puncture (LP) is often performed to assess for bacterial meningitis, though concomitant bacterial meningitis in the setting of UTI is uncommon1,2.

Previous studies have reported an association between UTI and sterile cerebrospinal fluid (CSF) pleocytosis3-8. The etiology of sterile CSF pleocytosis in febrile infants with UTI is unknown. One hypothesis is that systemic inflammation and cytokine release resulting from the bacterial UTI might cause CSF pleocytosis3; however, this has not been directly studied. Several authors have suggested that aseptic meningitis in infants with UTI might be caused by an undiagnosed concomitant viral infection, such as enterovirus (EV)6,9, though this hypothesis has not been proved. Prior studies either did not perform viral testing, only tested a small subset of patients for viral co-infection, or did not evaluate children during the enterovirus season3-8.

The University of Utah Department of Pediatrics in conjunction with Intermountain Healthcare developed a care process model for the management of febrile infants 1-90 days that includes molecular testing for enteroviruses10. We recognized an opportunity to examine the relationship between UTI, CSF pleocytosis and EV infection in a large population of febrile infants. The objectives of this study were to 1) determine the proportion of febrile infants with UTI who have CSF pleocytosis and 2) determine how often EV infection was also diagnosed in infants with UTI and CSF pleocytosis.

PATIENT AND METHODS

Human subjects protection

The Institutional Review Boards of Intermountain and the University of Utah approved this study. Informed consent was waived. The febrile infant evidence-based care process model (EB-CPM), implemented at Primary Children’s Medical Center in 2004 and in all Intermountain facilities in 200810 recommends EV testing during the months of June through November and in all febrile infants with CSF pleocytosis11. Use of the EB-CPM is voluntary and EV testing is performed at the discretion of the attending physician.

Identification and enrollment

Febrile infants 1-90 days of age with UTI were identified from the Intermountain enterprise data warehouse (EDW). The EDW contains clinical, laboratory, and administrative data for all Intermountain facilities. Intermountain is a not-for-profit, integrated healthcare system that provides care for >90% of Utah infants (personal communication Jim Bradshaw, Director of Strategic Planning, Intermountain Healthcare, Salt Lake City, UT). We developed a sensitive and specific definition for febrile infants based on reason for visit, admitting diagnosis, ICD-9, and APR DRG coding. This definition was previously validated against a prospectively collected sample.12

All infants 1-90 days of age who were evaluated for fever between 2004-2011 and who were diagnosed with UTI were identified and potentially eligible for inclusion in this study. UTI was defined as ≥50,000 cfu/mL of a at least one pathogenic organism13. To be included in this analysis, infants with UTI also had to have had CSF sampling for culture and cell count as well as EV testing of blood and/or CSF by polymerase chain reaction (PCR). CSF pleocytosis was defined as >18 WBC per high powered field (HPF) in infants <28 days and >9 WBC/HPF in infants 29-90 days.11 A traumatic lumbar puncture (LP), which could render the CSF profile difficult to interpret, was defined as one with RBC >10,000 cells/μL11.

Definite bacterial meningitis was defined as growth of a known pathogen in the CSF culture. Probable bacterial meningitis was defined as either: 1) positive blood culture associated with CSF pleocytosis and treatment consistent with bacterial meningitis; or 2) antibiotic pretreatment prior to LP, CSF pleocytosis, and treatment consistent with bacterial meningitis5.

Data collected

Basic demographic data were collected, including age, sex, visit month, and antibiotic pretreatment. Laboratory data collected included CSF profile (cell count and differential, protein, and glucose), Gram stain, and culture; urine and blood culture results; and EV testing. EV testing was performed at Intermountain Healthcare Central Laboratory on plasma and/or CSF by PCR (Xpert EV; Cepheid, Sunnyvale, CA). All data were abstracted from the Intermountain electronic data warehouse.

Statistical Analysis

Descriptive statistics were used to characterize the study population. CSF WBC values were compared between groups using linear regression. Statistical analyses were performed using STATA/IC 11.2 (College Station, TX).

RESULTS

During the study period, 162 febrile infants with UTI also had a full CSF evaluation and EV testing. The median age of the infants was 36 days; 39% were <29 days old. The majority of infants (133; 82%) were evaluated during EV season (June-November). Bacteria causing UTI included Escherichia coli (81%), Enterococcus spp. (9%), Klebsiella spp. (7%), Group B Streptococcus (2%), Enterobacter spp. (2%), Citrobacter spp. (<1%), Staphylococcus aureus (<1%), and Proteus mirabilis (<1%). Six (4%) had polymicrobial UTIs.

Fifty-seven infants with UTI (35%) had CSF pleocytosis. Of these, sixteen (28%) had a traumatic LP with >10,000 RBC/mm3. One of these infants was EV-positive, and one had probable bacterial meningitis. As CSF cell counts were uninterpretable, these 16 infants were excluded from further analyses. Four of the remaining 41 infants (10%) had definite (n=1) or probable (n=3) bacterial meningitis; all were due to E. coli, and all either had a positive CSF culture and/or were bacteremic. The median CSF WBC counts of infants with UTI and concomitant bacterial meningitis (3809 cells/μL; IQR 680-7326) were substantially higher when compared with EV-positive and other EV-negative infants.

Thirty-seven infants (23% of all infants with UTI) were defined as having sterile pleocytosis. Of these, 4 (11%) were EV-positive. The median CSF WBC counts were significantly higher in the four EV-positive infants (387 cells/μL; IQR 151-965) when compared with the 33 EV-negative infants with unexplained CSF pleocytosis (21 cells/μL; IQR 12-28) (p<0.001). For the remaining 33 EV-negative infants with sterile pleocytosis, no cause could be identified. Two (6%) received antibiotics before the LP was performed.

DISCUSSION

We report data for the largest cohort of febrile infants 1-90 days of age with UTI, CSF evaluation and molecular testing for EV infection. Ours is the first study in which all included infants with UTI were evaluated for concomitant EV infection by PCR. Similar to other investigators, we found that CSF pleocytosis was common in young infants with UTI. Of the 57 infants with CSF pleocytosis, a probable or definitive etiology could be identified in 42% of the infants and included traumatic LP (28%), bacterial meningitis (7%) and EV co-infection (7%). EV co-infection was an uncommon cause of sterile pleocytosis. The etiology for the majority of sterile CSF pleocytosis remains unexplained. Possible explanations include unidentified viral co-infection other than enterovirus and non-specific inflammation. It is also plausible that the venous drainage of urogenital system through the valveless Batson plexus during a UTI may result in minor attendant inflammatory cells in subarachnoid space.14

We documented CSF pleocytosis in 35% infants with UTI who had examination of CSF and EV testing. When infants with traumatic LP and probable or confirmed bacterial meningitis were excluded, 23% of infants with UTI had sterile CSF pleocytosis. This rate of sterile pleocytosis is somewhat higher than the 5-18% reported among previously published studies.3-8 However, the methodologies and definitions of pleocytosis and traumatic LPs varied among earlier studies.

Enterovirus was an uncommon cause of CSF pleocytosis in febrile infants with UTI. Only four infants with UTI and sterile CSF pleocytosis (11%) had EV infection documented by PCR of blood, CSF, or both. This finding is striking as most of the infants included in the study were evaluated during EV season, and EV infection is a common cause of CSF pleocytosis in febrile infants overall15,16 A previous study from our institution demonstrated that 33% of febrile infants with CSF evaluated in EV season were EV-positive.17

While the number of infants with documented EV infection and UTI was small (n=4), we documented that the CSF WBC counts were significantly higher in these infants than in infants with sterile CSF pleocytosis and negative PCR testing for EV infection. Three of the 4 infants with EV infection and UTI had CSF WBC counts >100 cells/μL. In contrast, EV-negative infants had mild CSF pleocytosis; 79% had CSF WBC counts <30 cells/μL. CSF WBC counts for both EV-positive and EV-negative infants were also markedly lower than the CSF WBC counts from infants with bacterial meningitis, the majority of whom had CSF WBC counts >1000 cells/μL.

While our study was not designed to evaluate the rate of coexisting bacterial meningitis in febrile infants with UTI, 4/162 (2.5%, 95% CI 0.68%-6.2%) had definite or probable bacterial meningitis. This rate is slightly higher than the 1.2-1.6% of infants with UTI and bacterial meningitis reported in other studies18-21. One potential explanation for this difference is that our sample may be biased towards younger or ill appearing infants. All infants in this analysis had both urine and CSF testing at the discretion of the attending physician. In our health system, only 50% of febrile infants overall have CSF testing as part of their evaluation for fever.10.

Our study has several limitations. First, it was performed retrospectively and represents a secondary analysis of data collected for another purpose10. Because we only included febrile infants who had undergone both LP and EV testing, our results may be biased toward younger and more ill-appearing infants; the actual proportion of febrile infants with UTI and CSF pleocytosis or UTI and meningitis may be lower. Finally we did not test CSF for all viruses that may cause pleocytosis. It is possible that infants with UTI and sterile CSF pleocytosis may be infected with other viruses, for example parechovirus22.

Despite these limitations, we are able to make several conclusions. First, our data suggest that EV coinfection is a relatively uncommon explanation for sterile CSF pleocytosis in febrile infants with UTI, even during EV season. Secondly, the majority of unexplained CSF pleocytosis in febrile infants with UTI is mild with WBC counts <30 cells/μL. Infants with sterile CSF pleocytosis and UTI usually can be distinguished from those with bacterial meningitis and may be able to be managed without prolonged antibiotics.5 Pleocytosis may be the result of non-specific and/or local inflammation or undetected other viral infection.

Sterile CSF pleocytosis occurs in febrile infants with UTI. Co-infection with enterovirus is a possible cause. We evaluated 57 infants with UTI and CSF pleocytosis. All had enterovirus testing by PCR. An explanation for pleocytosis was determined for 24 infants (42%). EV infection was detected in four and is an uncommon cause of CSF pleocytosis in infants with UTI.

Acknowledgements

The authors thank both the 2012 St. Jude/Pediatric Infectious Diseases Society Research Conference and the 2012 Pediatric Academic Societies Annual Meeting for allowing this research to be presented.

Sources of funding: EHD and CLB receive support from the H.A. and Edna Benning Foundation. AJB receives support from NIH/NIAID 1K23AI079401. CLB received support for this work from the NIH/ Eunice Kennedy Shriver NICHD K24-HD047249 and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 8UL1TR000105 (formerly UL1RR025764). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnotes

Conflicts of interest: AJB and CLB collaborate with BioFire Diagnostics, Inc. (formerly, Idaho Technology, Inc.), on several NIH and CDC-funded projects. AJB and CLB have intellectual property in BioFire Diagnostics, Inc. EHD, CS, and EKK have no conflicts of interest to report.

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