Early Prediction of COVID-19 Severity Using Extracellular Vesicles and Extracellular RNAs

The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission. After standard therapy without corticosteroids, 9 of the 31 patients developed severe COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. Among these markers, EV COPB2 has the best predictive value for severe deterioration of COVID-19 patients in this cohort. This type of information concerning functional extracellular component profiles could have great value for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy. ### Competing Interest Statement Mitsuru Miyato is a chief executive officer, and Takahiro Ochiya is a chief scientific advisor of International Space Medical Co., Ltd. The other authors have declared that no conflict of interest exists. ### Funding Statement This work was supported by International Space Medical Co., Ltd. ### 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: This retrospective study involving collection of COVID-19 serum samples was approved by the Institutional Review Board at The Jikei University School of Medicine (Number: 32-055(10130)). The protocol did not require informed consent, and patients were given the choice of opting out of the study. For collection of healthy control serum samples, this study was approved by the Institutional Review Board at The Institute of Medical Science, The University of Tokyo (Number: 28-19-0907). Written informed consent was provided by all healthy donors before sample acquisition, in accordance with Declaration of Helsinki principles. 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 GSE data will be opened.