Abstract
Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427–8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433–0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.
Highlights
The ongoing pandemic caused by the severe acute respiratory syndrome causing coronavirus 2 (SARS-COV-2) has resulted in close to 215 million documented infections and close to 4.5 million deaths
On comparing the relative abundance of circulating CD11c+HLA-DR- proinflammatory macrophages between the COVID-19 patients with mild diseases and patients who progressed to acute respiratory distress syndrome (ARDS), we found a prominent expansion of these cells in ARDS (Figures 1A, B), as reported by a number of previous studies as well [4,5,6]
We found no correlation between abundance of these cells in circulation in ARDS patients and the plasma levels of most of the cytokines, except for eotaxin (Pearson R = 0.3725, p = 0.0029), HGF (Pearson R = 0.2503, p = 0.0497), and IL-1a (Pearson R = 0.2588, p = 0.0423) (Figures 1C–E)
Summary
The ongoing pandemic caused by the severe acute respiratory syndrome causing coronavirus 2 (SARS-COV-2) has resulted in close to 215 million documented infections and close to 4.5 million deaths. The respiratory disease caused by SARS-COV-2, or COVID-19, progresses to acute respiratory distress syndrome (ARDS), often with fatal outcomes, in some patients [1]. Severe COVID-19 is characterized by systemic hyper-inflammation, the key manifestations being a systemic cytokine deluge and an abnormal myeloid expansion among circulating immune cells [2,3,4,5]. In addition to the hyper-inflammation, patients with severe COVID-19 present with intravascular coagulation as well as abnormal complement activation [6,7,8,9]. Risk-stratifying biomarkers, which can be probed early enough in severe COVID-19 patients, can be useful as pre-assessors for effective triage or intensive care in low-resource settings
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