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Neonatal Candida Meningitis: Significance of Cerebrospinal fluid Parameters and Blood Cultures

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Neonatal Candida Meningitis: Significance of Cerebrospinal fluid Parameters and Blood Cultures Journal of Perinatology (2007) 27, 97–100 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp ORIGINAL ARTICLE Neonatal Candida meningitis: significance of cerebrospinal fluid parameters and blood cultures M Cohen-Wolkowiez1, PB Smith1,2, B Mangum2, WJ Steinbach1, BD Alexander3, CM Cotten1, RH Clark4, TJ Walsh5 and DK Benjamin Jr1,2 1Department of Pediatrics, Duke University, Durham, NC, USA; 2Clinical Research Institute, Duke University Durham, NC, USA; 3Department of Medicine, Duke University, Durham, NC, USA; 4Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL, USA and 5Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA (CSF). However, lumbar punctures (LP) in infants are often Objective: The purpose of this study was to examine the frequency of delayed until after institution of empirical anti-fungal therapy or normal cerebrospinal fluid (CSF) parameters in Candida meningitis and until blood culture results are known to be positive, because of the the proportion of candidemia associated with Candida meningitis. delicate medical conditions of some infants, absence of specific 2 Study design: We evaluated the initial lumbar puncture results from clinical findings or assumptions of low risk of meningitis. infants discharged from 150 Neonatal Intensive Care Units between 1997 This delay in obtaining CSF places increased importance in and 2004. Candida meningitis was diagnosed by a positive CSF culture or interpretation of CSF parameters. In addition, recent studies have positive Gram stain for yeast. We calculated two-tailed P-values using shown that negative blood cultures are frequently found in infants 3 non-parametric testing, Mann–Whitney, Kruskal–Wallis or Fisher’s exact with meningitis. tests where appropriate. Little is known about the CSF parameters in infants with Candida meningitis. Normal CSF parameters (white blood cell Results: Twenty infants had culture-positive Candida meningitis. (WBC) count, red blood cell (RBC) count, glucose and protein) in Normal CSF parameters were found in 43% (3/7) of the infants with the presence of Candida meningitis have been reported in single Candida meningitis and only 37% (7/19) of them had positive blood center studies. Thus, the objective of this study was to describe the cultures for Candida. CSF parameters in infants with Candida meningitis identified Conclusion: Normal CSF parameters do not exclude the diagnosis of from a large multi-center cohort. neonatal Candida meningitis. The majority of infants in this cohort with Candida meningitis did not have evidence of candidemia at the time of diagnosis. Journal of Perinatology (2007) 27, 97–100. doi:10.1038/sj.jp.7211628; Methods published online 2 November 2006 We examined the initial LP results from a cohort of infants discharged from 150 NICUs managed by the Pediatrix Medical Keywords: newborn; fungal; prematurity; candidemia; meningoence- phalitis Group Inc. from 1997 to 2004. The data were obtained from an administrative database with a collection method described previously.3 Candida meningitis was diagnosed by a positive Introduction CSF culture or positive Gram stain for yeast. CSF samples were Invasive candidiasis is an increasingly important cause of mortality processed according to the individual hospital’s local laboratory and morbidity in the neonatal intensive care unit (NICU) as standards. Infants with CSF reservoirs and shunts were excluded survival of extremely preterm infants improves. Candida from the study. The Duke University Institutional Review Board meningitis complicates invasive candidiasis more often in infants provided permission to conduct this investigation. than older patients.1 Definitive diagnosis of Candida meningitis is We compared CSF parameters (WBC counts, RBC counts, determined by isolation of the organism in the cerebrospinal fluid glucose and protein) and demographic data from three distinct groups of patients: infants with culture-positive Candida Correspondence: Dr DK Benjamin Jr., Department of Pediatrics, Duke University, meningitis, infants with candidemia and culture-negative CSF for Duke Clinical Research Institute, PO Box 17969, Durham, NC 27705, USA. Candida, and infants with negative blood and CSF cultures. E-mail: [email protected] Received 17 July 2006; revised 20 September 2006; accepted 29 September 2006; published Normal CSF parameters for premature infants (<37 weeks) were 3 online 2 November 2006 defined as a WBC count <26/mm , glucose level >23 mg/dl and Infant Candida meningitis: CSF parameters M Cohen-Wolkowiez et al 98 a protein level <171 mg/dl.4 For infants with gestational age above candidemia and culture-negative CSF for Candida and 11 696 with 36 weeks, normal CSF parameters were defined as WBC count negative blood and CSF cultures (Table 1). The majority of infants <22/mm3 or less, glucose level >33 mg/dl and a protein level with Candida meningitis (85%, 17/20) and candidemia (71%, 55/ <120 mg/dl.4,5 77) had birth weights <1500 g. Of the 20 infants in the Candida We calculated two-tailed P-values using non-parametric testing, meningitis group, 19 had blood culture data and 17 had follow-up/ Mann–Whitney, Kruskal–Wallis or Fisher’s exact tests where outcome information available. Blood cultures were obtained appropriate, and used STATA 8.2 (Stata Corporation, College within 48 h before the CSF culture in 12/19 (63%) of the infants Station, TX, USA) for statistical analysis. and within 48 h after the CSF culture in 4/19 (21%) of the infants. Normal CSF parameters were found in 43% (3/7) of the infants with culture-positive Candida meningitis and 63% (20/32) of Results candidemic infants without Candida meningitis with complete sets The Pediatrix group provided care for 14 017 infants who received of CSF parameters, P ¼ 0.42. The median CSF WBC count in at least one LP. We evaluated the infants as three groups: 20 infants with culture-positive Candida meningitis was higher when infants with culture-positive Candida meningitis, 66 with compared to infants without meningitis (38 vs 9; P ¼ 0.047). The Table 1 Demographics and CSF parameters Culture-positive Candidemia and culture-negative Negative blood and CSF for Candida CSF for Candida CSF cultures N 20 66 11 696 Median gestational age (weeks) 25 26 37 Median birth weight (g) 670 874 2820 Male sex 10 (50%) 40 (60%) 6614 (66%) Delivery by C-section 8 (40%) 42 (64%) 6716 (58%) Mortalitya Died 7 (41%) 3 (6%) 180 (2%) Lived 10 (59%) 48 (94%) 10712 (98%) Total 17 51 10 892 Race Black 8 (40%) 15 (23%) 2117 (19%) Hispanic 6 (30%) 11 (17%) 3575 (32%) White 6 (30%) 37 (56%) 5100 (45%) Other 0 3 (4%) 514 (4%) CSF parameters WBC (count/mm3) (range) 38.5 (0–420)b 9 (0–191) 6 (0–90 000) 0 1 (12%) 3 (9%) 693 (11%) 1–21 1 (12%) 23 (65%) 4265 (69%) 22–100 4 (50%) 8 (23%) 778 (13%) >100 2 (25%) 1 (3%) 448 (7%) Glucose (mg/dl) (range) 47 (22–170)b 48 (10–102) 49 (0–1089) 0–23 1 (14%) 4 (11%) 131 (2%) 24–50 4 (57%) 16 (43%) 3140 (53%) >50 2 (29%) 17 (46%) 2689 (45%) Protein (mg/dl) (range) 115 (68–1860)b 141 (54–600) 114 (3–117 000) 0–100 2 (29%) 13 (33%) 2343 (39%) 101–170 3 (42%) 16 (41%) 2492 (42%) >170 2 (29%) 10 (26%) 1113 (19%) Abbreviations; CSF, cerebrospinal fluid; WBC, white blood cell. aPatients with available follow-up data. bMedian. Journal of Perinatology Infant Candida meningitis: CSF parameters M Cohen-Wolkowiez et al 99 values for CSF glucose and protein were neither substantively nor Study strengths are the large number of LPs evaluated and the statistically different among the three groups, P ¼ 0.86 and ability to examine blood culture results from a diverse group of P ¼ 0.11, respectively. Only 37% (7/19) of infants with NICUs. This study also represents information obtained under culture-positive Candida meningitis had a positive blood culture current care practices. Primary study limitations include for Candida. retrospective design, missing CSF parameter data and lack of anti-fungal data before LP. Candida meningitis can result in significant mortality in Discussion infants. Although the index of suspicion that an infant with Appropriate interpretation of initial CSF parameters in infants with candidemia may also have Candida meningitis should be suspected meningitis is critical in the decision-making process of increased if the CSF WBC is elevated, clinicians should be cautious the practicing clinician. In our study, normal CSF parameters in presuming absence of CNS candidiasis in the candidemic infant (WBC count, glucose and protein) were found in nearly half (3/7) with normal CSF parameters. Because many infants with Candida of infants with culture-proven Candida meningitis. Therefore, meningitis do not exhibit growth of Candida in the blood, normal CSF parameters do not exclude Candida meningitis in the performing a CSF examination at the time of sepsis evaluation in neonatal population. clinically stable infants is important. Finally, these data emphasize Unremarkable CSF parameters in the presence of Candida CNS the need for improved diagnostic interventions for the detection of infection are consistent with the pathophysiology of disease, invasive candidiasis. because candidiasis of the CNS develops as a meningoencephalitis with subcortical and cortical granulomas, parenchymal abscesses and vasculitis.6,7 In a report by Faix et al.,8 only 50% (5/10) of the infants with culture-proven Candida meningitis had CSF WBC Acknowledgments counts higher than 25 cells/mm3. A similar percentage of infants This work was supported by a research agreement between Pediatrix Inc. and with elevated CSF WBC count (52%, 9/17) was observed in another Duke University Medical Center. Dr Smith received support from NIH T32 AI cohort of infants with definite Candida meningitis,9 and an even 052080 and Dr Benjamin received support from HD044799-01 and the Thrasher lower percentage (20%, 2/10) was found in another series.10 Research Fund.
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