Is there a serum proteome signature to predict mortality in severe COVID-19 patients? (preprint)

Here we recorded serum proteome profiles of 33 COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later timepoints. We focused on serum proteins different in abundance between the group of survivors and non-survivors and observed that a rather small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, HRG and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3 and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also did show opposite trends in protein abundance during disease progression. This panel of eight proteins, complemented with a few more, may represent a panel for mortality risk assessment and eventually even for treatment, by administration of exogenous proteins possibly aiding survival. Such administration is not unprecedented, as administration of exogenous inter-α-trypsin inhibitors is already used in the treatment of patients with severe sepsis and Kawasaki disease. The mortality risk panel defined here is in excellent agreement with findings in two recent COVID-19 serum proteomics studies on independent cohorts, supporting our findings. This panel may not be unique for COVID-19, as some of the proteins here annotated as mortality risk factors have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients (preprint)

Background: Evaluation of biomarkers in the context of ARDS is used to detect the presence of endothelial and/or alveolar epithelial injuries. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aim of this study was to evaluate whether the trends in plasma concentration of the biomarkers mentioned above were different in survivors and non-survivors of COVID-19-related ARDS. Furthermore, we compared the expression of biomarkers of vascular and endothelial injury in patients with COVID-19-related ARDS and classical ARDS. Methods: This prospective study was performed in two COVID-19 dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 10 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7±2 days (T2) and 14±2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p=0.04 and p=0.03, respectively) whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS, than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19 related ARDS (all p<0.001). Conclusions: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration: NCT04343053 Date of registration: April 13, 2020