Detection of (1,3)-β-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis

Abstract

Background Central nervous system (CNS) histoplasmosis is a life-threatening condition, and represents a diagnostic and therapeutic challenge. Although CSF (1,3)-β-d-glucan (CSF BDG) is available as a biologic marker for diagnosis of fungal meningitis, there are limited data on its use for diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection using the Fungitell assay in patients with CNS histoplasmosis and controls.Methods Patients were classified as cases if there was CNS inflammation (CSF WBC ≥ 5 mm3/ml) plus laboratory confirmation of H. capsulatumin CNS samples or from extra-CNS sites with no alternative etiology for CSF pleocytosis. Controls were patients with histoplasmosis but no evidence of CNS involvement, an alternative diagnosis, or other fungal meningitis.ResultsIn total, 47 cases and 153 controls were evaluated (Table 1). Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. CSF BDG was positive in 25 (53.2%) cases using a level of ≥80 pg/ml, the median CSF BDG level was 140.5 pg/ml (range from <31 to 500 pg/ml). The detection of CSF BDG level ≥80 pg/ml was not associated with positive CSF Histoplasma antigen (P = 0.28) or positive CSF Histoplasma culture (P = 0.56). The sensitivity for detection of CSF BDG was 53.2% and the specificity was 87.3%, compared with 78.7% (P = 0.009) and 96.4% (P = 0.003), respectively, for detection of antigen. CSF BDG was positive in 20 of 153 (13.1%) patients in the control group. Seven of 11 (63.6%) other CNS fungal meningitis cases (five Cryptococcus, two Aspergillus, two Blastomyces, one Candida, and one suspected fungal meningitis) had CSF BDG ≥80 pg/ml.Conclusion A positive CSF BDG supports the diagnosis of fungal meningitis but cannot distinguish among the different etiologies. The sensitivity and specificity of detection of CSF BDG was lower than that of antigen detection.Table 1:Characteristic of the study patientsParameterCNS histoplasmosisControlsa P-valueImmunocompromised23/47 (48.9%)67/153 (43.8%)0.54CSF BDG > 80 pg/ml25/47 (53.2%)b20/153 (13.1%)c<0.0001CSF Histoplasma antigen positive37/47 (78.7%)25/142 (3.5%)3<0.0001CSF culture positive9/44 (20.5%)11/117 (9.4%)0.058 aControl included five Cryptococcus, two Aspergillus, two Blastomyces, one Candida, and one suspected fungal meningitis. b P-value = 0.009; cP-value = 0.003.Disclosures L. J. Wheat, MiraVista: President and owner, equity and Salary

Methods for Rapid Diagnosis of Meningitis Etiology in Adults

“…1,3-Beta-D-glucan 1,3-Beta-D-glucan (BDG) measurement in CSF has been used to detect a variety of fungi including all fungi discussed below, yet specificity for any individual fungi is inadequate [14,124,125]. Although it was previously thought that Cryptococcus did not release sufficient BDG for detection, this was disproven by Rhein and colleagues who found that among HIV-infected patients with cryptococcal meningitis, BDG showed a sensitivity of 89% and specificity of 85% compared with cryptococcal antigen detection with higher BDG levels being associated with mortality [11,125,126].…”

“…There remains a FDA-required black-box label incorrectly stating that Cryptococcus does not produce BDG. CSF BDG has also been studied for Histoplasma meningitis with a sensitivity of 53% and specificity of 87% [124]. Thus, while BDG may have utility in steering clinicians towards fungal meningitis -BDG is not able to reliably diagnose any particular fungal pathogen.…”

“…Histoplasma meningitis CSF culture is the standard for diagnosis of Histoplasma meningitis but is only positive in 19-65% of cases and growth can take up to 4 weeks [15,27,124,[128][129][130][131]. Culture can be improved by using at least three samples of at least 10 ml of CSF -impossible in most cases [15,128,131,132].…”

Single and Repeated Episodes of Candida Species Isolated From Cerebrospinal Fluid for Diagnosing Probable Candida meningitis

“…Some studies revealed that CSF (1,3)-β-D-glucan was a surrogate marker for PCM, and the persistence of (1,3)-β-D-glucan in CSF was associated with the clinical and microbiological failure of PCM (Lyons et al, 2015;Ceccarelli et al, 2016;Farrugia et al, 2016). Although elevated CSF (1,3)-β-D-glucan was not specifically present in CNS infections of Aspergillus, Cryptococcus and Histoplasma (Rhein et al, 2014;Chen et al, 2017;Myint et al, 2018), CSF (1,3)-β-D-glucan testing may still be a useful surrogate marker of C. meningitis (Davis et al, 2020). Although it seemed that a single episode of CSF Candida was insufficient for PCM diagnosis, a study indicated that normal CSF parameters were found in 43% (3/7) of infants with C. meningitis, and only 37% (7/19) of them had positive blood cultures for Candida (Cohen-Wolkowiez et al, 2007).…”

<p>HIV-Associated Histoplasmosis: Current Perspectives</p>

“…Another study assessed the role of the MVista ® IgG and IgM antibody EIA 66 and of 1,3-beta-D-glucan detection 85 in CSF for diagnosis of meningitis. Culture of CSF was positive in 19.1% (9 of 47).…”