Utility of Measuring (1,3)-β- d -Glucan in Cerebrospinal Fluid for Diagnosis of Fungal Central Nervous System Infection

Abstract

(1-3)-␤-D-Glucan (BDG) from cerebrospinal fluid (CSF) is a promising marker for diagnostic and prognostic aid of central nervous system (CNS) fungal infection, but its relationship to serum values has not been studied. Herein, we detected BDG from CSF at levels 2-fold lower than those in serum in patients without evidence of fungal disease but 25-fold higher than those in in serum in noncryptococcal CNS fungal infections. CSF BDG may be a useful biomarker in the evaluation of fungal CNS disease.is a fungal cell wall polysaccharide (Cryptococcus and mucoralean fungi generally excepted). Circulating BDG is sometimes detectable at low levels (Ͻ60 pg/ml) in blood of asymptomatic individuals and is elevated in patients with invasive fungal infections (1). The U.S. Food and Drug Administration (FDA) has approved testing of BDG in serum to aid in diagnosis of invasive fungal infections. Clinical studies have demonstrated that the test marketed in the United States has a sensitivity of 75 to 77% and a specificity of 60 to 80% in the diagnosis of candidiasis in intensive care unit patients and aspergillosis in lung transplant patients with a cutoff value of Յ60 pg/ml as negative and Ն80 pg/ml as positive (2-4).Cerebrospinal fluid (CSF) BDG measurement has not been validated. Its utility was first described for a nonneutropenic rabbit model of experimental hematogenous Candida meningoencephalitis (5). Lyons et al. (6) and Litvintseva et al. (7) showed its diagnostic and prognostic utility during the 2012 U.S. fungal central nervous system (CNS) infection outbreak. Our study further explores the utility of CSF BDG and the relationship between serum and CSF BDG in CNS fungal and nonfungal disease.We selected CSF and serum samples collected for routine care between 2007 and 2013 and frozen as part of a research protocol approved by Johns Hopkins Institutional Review Board. We selected subjects whose CSF and serum were collected within 24 h of one another. There was only one serum and one CSF specimen available per patient. Diagnoses were confirmed by chart review and were simultaneous with the timing of sample acquisition.Demographic information, including gender, age, race, clinical diagnosis, and indication for lumbar puncture, was documented. Pertinent clinical information gathered included history of fungal infection or other CNS infection, HIV status, and history of organ transplantation or other evidence of immunosuppression. Culture, serology, histopathology, and neuroimaging data were collected for diagnostic purposes. Fungal infections were defined as proven, probable, or possible based on EORTC/MSG criteria (8) or CDC definitions for outbreak-associated meningitis (9).Sterilely collected CSF and serum specimens had been frozen to Ϫ80°C and were shipped on dry ice to the Beacon Diagnostics Laboratory for testing via the Fungitell assay (Associates of Cape Cod, Inc., East Falmouth, MA). All assays were performed in a biosafety cabinet that had not been used to manipulate fungal cultures. Glucan-free dilution tubes an...

Cerebrospinal Fluid (1,3)-Beta- d -Glucan Testing Is Useful in Diagnosis of Coccidioidal Meningitis

“…In comparison with our sensitivity of 96%, this suggests that in a compartmentalized infection, sensitivity is increased. This is further supported by observations in several studies comparing concurrent CSF and serum ␤-glucan values, which showed that CSFs had a higher percentage of positive results than sera and/or the titers in CSF were higher (13,14,16,18).…”

“…Eighteen patients with bacterial or viral meningitis with pleocytosis had a CSF range of Ͻ4 to 109 pg/ml (14), and 19 and 44 patients without fungal meningitis, not characterized in detail, had CSF values of 7 to 115 and Ͻ31 pg/ml, respectively (12,13). Coupled with our range of Ͻ3.9 to 103 pg/ml, patients without fungal meningitis appear to have CSF values that are remarkably similar.…”

“…The results in a series of pediatric cases of Candida and Aspergillus meningitis gave a range of 86 to 1,158 pg/ml (12). Five cases of noncoccidioidal fungal meningitis were reported to have a range of 103 to 523 pg/ml (13), and a report of 3 cases of noncoccidioidal, noncryptococcal fungal meningitis indicated a range of 110 to 1,524 pg/ml (14). When considered together with our range of 18 to 3,300 pg/ml, different fungal meningitides appear to have a wide, overlapping, and somewhat similar range of positivity.…”

2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis*

“…Measurement of CSF (1, 3)-β-D-glucan using the manufacturer's cutoff of ≥80 pg/mL was highly sensitive (96%) and specific (95%) for the diagnosis of proven fungal meningitis associated with contaminated methylprednisolone injections [90]. Another study has also demonstrated the usefulness of CSF (1, 3)-β-D-glucan for diagnosing or excluding fungal CNS infection [91].…”

Laboratory Diagnosis of Central Nervous System Infection

“…Elevated BDG in serum as well as CSF is associated with fungal infections; measuring the levels of BDG might be a useful biomarker in the evaluation of fungal CNS disease 36 . It was recently reported that patients receiving effective antifungal therapy showed reduction in CSF BDG concentration (<31pg/ml), and for this reason BDG titers in CSF can be as a useful biomarker in monitoring response to treatment 37 .…”