ABSTRACT
INTRODUCTION: Complex critical syndromes like sepsis and COVID-19 may be composed of underlying subclasses, or 'endotypes,' which may respond differently to treatment. We previously reported the discovery and validation of a 33-mRNA host response classifier which defined three sepsis endotypes across 1,300 patients with bacterial sepsis at hospital or ICU admission. Here, we aimed to test whether our 33-mRNA bacterial sepsis endotypes classifier recapitulates the same clinical and immunological endotypes in COVID-19. METHODS: In this prospective, single-center observational cohort study, we recruited adult patients with RT-PCRconfirmed COVID-19 within 24 hours of admission to an Athens, Greece hospital. RNA was extracted from whole blood collected in PAXgene RNA tubes, and then profiled on the NanoString nCounter® platform to quantify the 33 mRNAs. The endotypes classifier then assigned one of three endotypes (Inflammopathic, Adaptive, or Coagulopathic) to each patient. We tested endotype status against other clinical parameters including lab values, severity scores, and outcomes. RESULTS: We enrolled 71 patients with COVID-19, of which 33 went on to severe respiratory failure (SRF), of which 6 (8%) died. Patients were assigned as Inflammopathic (34%), Adaptive (39%), or Coagulopathic (27%);Adaptive patients had lower rates of SRF and no mortalities. Coagulopathic and Inflammopathic endotypes had 12% and 16% mortality rates. The Coagulopathic group was significantly associated with D-dimers, and the Inflammopathic group showed high clinical severity and highest C-reactive protein and IL-6 levels. CONCLUSIONS: Our predefined 33-mRNA endotypes classifier recapitulated immune phenotypes in viral sepsis (COVID-19) despite its prior training and validation only in bacterial sepsis. Further work should focus on continued validation of the endotypes and their interaction with immunomodulatory therapy. If confirmed with future studies, the 33-mRNA classifer could be used as a companiondiagnostic test to guide a precision-medicine-based intervention.