Unexpected Variability in Laboratory and Clinical Assays Used to Quantify Cryptococcus neoformans Polysaccharide

The detection and quantification of cryptococcal capsular polysaccharide (PS) antigen in body fluids is useful for the diagnosis of cryptococcosis. We compared the sensitivity of 4 assays for measuring the amount of cryptococcal PS and 2 clinical assays (lateral flow assay [IMMY] and the cryptococcal latex agglutination assay [Remel]) using the PS of 4 single-motif-expressing Cryptococcus strains. These showed relatively consistent laboratory assay interstrain sensitivity with significant interstrain variation, with the more sensitive clinical assays showing variation consistent with antigenic differences. Analysis of lateral flow assay false-negative isolates reveals that cryptococcal PS motif expression is not recognized by the antibodies used in the assay. These results suggest that strain variation in PS structure affects the sensitivity of the various quantification tests, while antigen-antibody matching is essential to avoid false-negative results in cryptococcal antigen testing of bodily fluids. Including antibodies with higher specificity in clinical assays could reduce false-negative results.