Plasma 1,3-β-d-glucan levels predict adverse clinical outcomes in critical illness
Georgios D. Kitsios, … , Bryan J. McVerry, Alison Morris
Georgios D. Kitsios, … , Bryan J. McVerry, Alison Morris
Published June 15, 2021
Citation Information: JCI Insight. 2021;6(14):e141277. https://doi.org/10.1172/jci.insight.141277.
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Clinical Medicine Infectious disease Microbiology

Plasma 1,3-β-d-glucan levels predict adverse clinical outcomes in critical illness

Abstract

BACKGROUND The fungal cell wall constituent 1,3-β-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 with healthy controls, patients with ARF had significantly higher BDG levels (median [IQR], 26 pg/mL [15–49 pg/mL], P < 0.001), whereas patients with ARF with high BDG levels (≥40 pg/mL, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (OR [CI], 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.CONCLUSION 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.FUNDING University of Pittsburgh Clinical and Translational Science Institute, COVID-19 Pilot Award and NIH grants (K23 HL139987, U01 HL098962, P01 HL114453, R01 HL097376, K24 HL123342, U01 HL137159, R01 LM012087, K08HK144820, F32 HL142172, K23 GM122069).

Authors

Georgios D. Kitsios, Daniel Kotok, Haopu Yang, Malcolm A. Finkelman, Yonglong Zhang, Noel Britton, Xiaoyun Li, Marina S. Levochkina, Amy K. Wagner, Caitlin Schaefer, John J. Villandre, Rui Guo, John W. Evankovich, William Bain, Faraaz Shah, Yingze Zhang, Barbara A. Methé, Panayiotis V. Benos, Bryan J. McVerry, Alison Morris

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Figure 6

Patients with a high plasma BDG levels (≥40 pg/mL) at baseline had worse 30-day survival after intubation compared with patients with low (<40 pg/mL) BDG levels.

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Patients with a high plasma BDG levels (≥40 pg/mL) at baseline had worse...
(A) Kaplan-Meier curve for 30-day survival showing worse outcome after intubation for patients with high BDG levels (≥40 pg/mL) at baseline. HR and 95% CI from a Cox proportional hazards model adjusted for age, sex, and SOFA score at baseline. Further adjustments of the Cox model by markers of epithelial permeability (RAGE and FABP-2) did not affect the significance or strength of the HR for BDG on 30-day survival. (B) When patients with BDG of 40 pg/mL or higher were further stratified by standard cutoff points for clinical diagnosis of IFI, we found that BDG of 80 pg/mL or higher (positive test) had significantly worse survival than patients with BDG less than 40 pg/mL (adjusted HR 2.43 [1.54–3.85, P < 0.0001), whereas patients with intermediate range BDG levels (40–59 or 60–79 pg/mL) had similar survival between the other 2 groups.