Plasma 1,3-β-d-glucan levels 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 that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically-ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes. Methods:We enrolled 453 mechanically-ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity and epithelial permeability biomarkers in serially collected plasma samples.Results: Compared to healthy controls, ARF patients had significantly higher BDG levels (median [interquartile-range] 26 [15-49]pg/ml, p<0.001), whereas ARF patients with high BDG levels (≥40pg/ml, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (odds ratio [confidence interval] 2.88 [1.83-4.54], p<0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted p<0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19.Conclusions: BDG measurements offered prognostic information in critically-ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.

Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation

“…Although modest compared to levels observed during invasive fungal infections, the levels of plasma β-glucan we observed in two cohorts of PASC (Fig. 2-3) may be clinically significant and with a potential to exacerbate a pro-inflammatory state, as suggested by a recent study (57). In that study (not focus on COVID-19), β-glucan levels in plasma ≥40 pg/ml were associated with higher inflammation, fewer ventilator-free days, and worse survival in patients with acute respiratory failure (57).…”

“…2-3) may be clinically significant and with a potential to exacerbate a pro-inflammatory state, as suggested by a recent study (57). In that study (not focus on COVID-19), β-glucan levels in plasma ≥40 pg/ml were associated with higher inflammation, fewer ventilator-free days, and worse survival in patients with acute respiratory failure (57). β-glucans are known to induce inflammation by activating the NF-κB pathway following binding to the Dectin-1 receptor (60-62).…”

“…2B-E ). Recently, it was shown that plasma β-glucan levels ≥40 pg/ml are clinically significant and associated with higher inflammation and worse survival in patients with acute respiratory failure (57). In the UCSF LIINC cohort, 33% of volunteers experiencing PASC had β-glucan levels ≥40 pg/ml, whereas only 7.1% of non-PASC volunteers had β-glucan ≥40 pg/ml.…”

“…The source of β-glucan in the plasma is not clear. Fungal translocation during illness can occur from both the gut and the lung (57). Examining the contribution of the gut microbiome (using stool samples and intestinal biopsies) and lung microbiome (using sputum and/or bronchoalveolar lavage) will be needed to determine the source of the fungal translocation during PASC and the fungal species contributing to it.…”

Neutrophil Extracellular Traps in Severe SARS-CoV-2 Infection: A Possible Impact of LPS and (1→3)-β-D-glucan in Blood from Gut Translocation

“…The results were demonstrated in relative quantitation of the comparative threshold method (2 −ΔΔCt ) as normalized by β-actin. Because of the LPS and BG in the COVID-19 serum [ 38 , 39 , 40 ] and pathogen-molecule-activated NETs (9), the in vitro test was conducted on normal neutrophils. As such, neutrophils (5 × 10 4 cells/well) were placed onto Poly-L-Lysine-coated (Sigma-Aldrich) glass coverslips, incubated at 37 °C, 5% CO 2 with BG using whole glucan particle (WGP) (the purified BG from Saccharomyces cerevisiae) (Biothera, Eagan, MN, USA) at 10 μg/mL with or without LPS (Escherichia coli 026: B6) (Sigma-Aldrich), at 10 μg/mL for 2 h, before determination of supernatant dsDNA, PAD-4 expression, and DAPI nuclear staining.…”