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

Background The fungal cell-wall constituent ([1][1],[3][2])-β-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. Funding support National 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)]. ### Competing Interest Statement GDK receives research funding from Karius, Inc. The other authors have no competing interests to declare. MF and YZ are employed by the manufacturer of the BDG assay (Associates of Cape Cod, Inc, East Falmouth, MA, USA) used in this study (Fungitell). ### Funding Statement Funding support: National 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)]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Pittsburgh Institutional Review Board approved the study (STUDY19050099) and written informed consent was provided by all participants or their surrogates in accordance with the Declaration of Helsinki. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings will be available on Github at https://github.com/MicrobiomeALIR following acceptance of this manuscript for publication. * ARDS : Acute Respiratory Distress Syndrome ALIR : Acute Lung Injury and Biospecimen Repository AKI : Acute kidney injury CHF : Congestive heart failure ICU : Intensive care unit IL : Interleukin ITS : Internal transcribed spacer IFI : Invasive fungal infection P:F ratio : Ratio of partial pressure of arterial oxygen [P] and fraction of inspired oxygen [F] RAGE : Receptor of advanced glycation end-products SOFA : Sequential Organ Failure Assessment ST-2 : Suppression of tumorigenicity-2 TNFR1 : Tumor necrosis factor receptor 1 UPMC : University of Pittsburgh Medical Center VFD : Ventilator-free days [1]: #ref-1 [2]: #ref-3