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

BackgroundThe 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. MethodsWe 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. ResultsA 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). ConclusionsThis 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. Funding supportNational Institutes of Health [K23 HL139987 (GDK); U01 HL098962 (AM); P01 HL114453 (BJM); R01 HL097376 (BJM); K24 HL123342 (AM); U01 HL137159 (DVM, PVB); R01 LM012087 (DVM, PVB); R01 HL142084 (JSL); R01 HL136143 (JSL); F32 HL137258 (JWE); F32 HL142172 (WB); K08 HS025455 (IJB); K23 GM122069 (FS)].