Improvements in the immunologic tests performed on cerebrospinal fluid have increased the sensitivity and reduced the turnaround time for diagnosis of central nervous system histoplasmosis over prior antigen and antibody detection methods and culture.

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-β-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to<31 pg/ml for all controls ( < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis ( = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of meningitis.

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

Summary Background/Objectives Antibody detection is commonly used for diagnosis of histoplasmosis, and cross‐reactions have been recognised due to endemic mycoses but not cryptococcosis. We observed cross‐reactions in an anti‐Histoplasma antibody enzyme immunoassay (EIA) in the cerebrospinal fluid (CSF) from a patient with cryptococcal meningitis and sought to assess the risk of cross‐reactive anti‐Histoplasma antibodies in persons with cryptococcal meningitis. Methods An anti‐cryptococcal antibody EIA was developed to measure CSF antibody response in HIV‐infected subjects from Kampala, Uganda and previously healthy, HIV‐negative subjects at the National Institutes of Health (NIH) with cryptococcal meningitis. Specimens were tested for cross‐reactivity in assays for IgG anti‐Histoplasma, anti‐Blastomyces and anti‐Coccidioides antibodies. Results Among 61 subjects with cryptococcal meningitis (44 Kampala cohort, 17 NIH cohort), elevated CSF anti‐cryptococcal antibody levels existed in 38% (23/61). Of the 23 CSF specimens containing elevated anti‐cryptococcal antibodies, falsely positive results were detected in antibody EIAs for histoplasmosis (8/23, 35%), coccidioidomycosis (6/23, 26%) and blastomycosis (1/23, 4%). Overall, 2% (2/81) of control CSF specimens had elevated anti‐cryptococcal antibody detected, both from Indiana. Conclusions Cryptococcal meningitis may cause false‐positive results in the CSF for antibodies against Histoplasma, Blastomyces and Coccidioides. Fungal antigen testing should be performed to aid in differentiating true‐ and false‐positive antibody results in the CSF.