Circulating microRNAs as Biomarkers of COVID-19 Severity

RATIONALE: The identification of minimally invasive and easily-accessible biomarkers to support the management of coronavirus disease 2019 (COVID-19) in hospitalized patients constitutes a hot topic in clinical research. MicroRNAs (miRNAs) have been proposed as clinical indicators to assist in medical decision-making. Here, we aimed to examine the circulating miRNA profile of hospitalized COVID-19 patients and to evaluate its potential as a source of biomarkers for the management of the disease. METHODS: Observational, prospective and multicenter study which included 84 patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, recruited during the first pandemic wave in Spain (March-May 2020). Patients were stratified according to disease severity: hospitalized patients admitted to the clinical wards without requiring critical care (n = 47) and hospitalized patients admitted to the ICU (n = 37). An additional study considering ICU non-survivors (n=17) and survivors (n = 20) was performed. Expression profiling of 41 miRNAs was performed in plasma samples using RT-qPCR. The panel included miRNAs associated with: i) immune/inflammatory response;ii) lung damage;iii) respiratory viral infections;iv) myocardial damage;v) coagulation. Quality control was performed using spike-ins and hemolysis tests. Predictive models were constructed using a variable selection process based on LASSO regression. RESULTS: Ten circulating miRNAs were deregulated in ICU compared to ward patients. LASSO analysis identified a signature of three miRNAs that displayed an optimal discrimination ability to distinguish between ICU and ward patients (AUC = 0.88) (Figure 1A). Among ICU patients, six miRNAs were downregulated when comparing nonsurvivors to survivors. A signature based on two miRNAs was found to be a relevant predictor of mortality during ICU stay (AUC = 0.84) (Figure 1B). The discrimination potential of the miRNA signature was higher than the observed for clinical laboratory parameters such as leukocyte counts (including neutrophil count, lymphocyte count and the neutrophil-tolymphocyte ratio), CRP or D-dimer (maximum AUC for these variables = 0.76). CONCLUSIONS: The severity of COVID-19 impacts on the circulating miRNA profile. The results suggest the potential usefulness of the circulating miRNA signature for the management of the disease over contemporaneous tests, at least in ICU patients.