Performance of repeated measures of (1-3)-β-D-glucan, mannan antigen and anti-mannan antibodies for the diagnosis of Invasive Candidiasis in ICU patients: a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial

Background We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan (BDG), mannan-antigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population. Methods This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit-acquired sepsis, multiple Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80 and >250 pg/mL), mannan-Ag (>125 pg/mL), and antimannan-Ab (>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2). Results Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71-2.02). Conclusions Among high-risk patients, a first measurement of BDG >80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup.