Plasma (1→3) β-d-glucan levels are associated with host inflammatory responses and predict adverse clinical outcomes in critical illness

Abstract

Background: The fungal cell-wall constituent (1,3)-beta-d-glucan (BDG) is a pathogen-associated molecular pattern (PAMP) that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically-ill patients may translocate into the systemic circulation and thus be associated with host inflammatory responses and outcomes. Methods: We enrolled 453 mechanically-ventilated patients with acute respiratory failure with no evidence of invasive fungal infection (IFI). From serial plasma samples, we measured BDG, innate immunity and epithelial permeability biomarkers. From lower respiratory tract and stool samples we quantified bacterial and fungal DNA load using culture-independent techniques. Results: A positive BDG test (>60pg/ml) at baseline was detected in 19% of patients. BDG levels were significantly associated with markers of innate immunity (interleukin-6, tumor necrosis factor receptor-1 and procalcitonin), epithelial barrier disruption (receptor for advanced glycation end-products and fatty-acid binding protein-2, for lung and gut respectively) and with higher probability of classification in an adverse prognosis hyperinflammatory subphenotype (all p<0.05). No differences in fungal or bacterial DNA load were found by BDG test positivity. Positive BDG testing was associated with higher incidence of acute kidney injury, fewer ventilator free days and worse 30-day survival (adjusted p<0.05). Patients with positive BDG test on follow-up sampling (>3 days from intubation) had higher mortality than patients with persistently negative test on follow-up (p<0.05). Conclusions: This is the first study to demonstrate the prognostic role of BDG in critically ill patients with no evidence of IFI. Translocation of BDG into systemic circulation may contribute to inflammation and clinical outcomes.

Host-Response Subphenotypic Classification with A Parsimonious Model Offers Prognostic Information in Patients with Acute Respiratory Failure: A Prospective Cohort Study.

“…These hostresponse biomarkers were classi ed into those measuring innate immune responses (interleukin [IL]-6, IL-8, IL-10, fractalkine, soluble tumor necrosis factor receptor-1 [TNFR1], suppression of tumorigenicity-2 [ST-2]) (6,(17)(18)(19)(20), epithelial injury (receptor of advanced glycation end-products [RAGE]) (21,22), endothelial injury (angiopoietin-2 [ang-2]) (23)(24)(25), and response to bacterial infections (procalcitonin and pentraxin-3) (26)(27)(28). We also measured 1-3-beta-D-glucan (BDG), a fungal cell-wall constituent shown to correlate with in ammatory biomarkers, using the commercially available Fungitell® Limulus Amebocyte Lysate (LAL) assay (Associates of Cape Cod, Inc, East Falmouth, MA, USA) at the manufacturer's facility (29).…”