Cryptococcal meningitis is a cause for cross-reactivity in cerebrospinal fluid assays for anti-Histoplasma, anti-Coccidioides and anti-Blastomyces antibodies

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.