Abstract

BACKGROUND: Asymptomatic cryptococcal antigenemia (positive blood cryptococcal antigen [CrAg]) is associated with increased mortality in HIV-positive individuals even after adjusting for CD4 count and despite receiving antifungal treatment. The association of antibody immunity with mortality in HIV-positive adults with cryptococcal antigenemia is unknown. METHODS: Cryptococcus spp. capsular glucuronoxylomannan (GXM)- and naturally occurring β-glucans (laminarin, curdlan)-binding antibodies were measured in blood samples of 197 South Africans living with HIV who underwent CrAg screening and were prospectively followed up to 6 months. Associations between antibody titers, CrAg status and all-cause mortality were sought using logistic and Cox proportional hazards regression, respectively. RESULTS: Compared to CrAg-negative (n = 130), CrAg-positive individuals (n = 67) had significantly higher IgG1 (median, 6,672 [interquartile range, IQR, 4,696-10,414] vs. 5,343 [3,808-7,722]μg/ml; P = 0.007), IgG2 (1,467 [813-2,607] vs. 1,036 [519-2,012]μg/ml; P = 0.01), GXM-IgG (1:170 [61-412] vs. 1:117 [47-176]; P = 0.0009) and lower curdlan-IgG (1:47 [11-133] vs. 1:93 [40-206]; P = 0.01) titers. GXM-IgG associated directly with cryptococcal antigenemia adjusted for CD4 count and antiretroviral therapy use (odds ratio, 1.64 for each log increase in titer; 95% confidence interval [CI], 1.21-2.22). Among CrAg-positive individuals, GXM-IgG inversely associated with mortality at 6 months adjusted for CD4 count and active or prevalent tuberculosis (hazard ratio, 0.50; a two-fold reduction per log increase in titer; 95% CI, 0.33-0.77). CONCLUSIONS: The finding of an inverse association of GXM-IgG with mortality in CrAg-positive individuals suggests that GXM-IgG titer may have prognostic value in such individuals. Prospective longitudinal studies of antibody levels to investigate this hypothesis and identify mechanisms by which antibody may protect against mortality are warranted.