ABSTRACT
INTRODUCTION: Transcriptome-derived sepsis subphenotypes, termed 'adaptive', 'inflammopathic' and 'coagulopathic', have been reliably identified in sepsis cohorts, however plasma proteomics in these groups have not been well characterized. We hypothesized that inflammatory and vascular injury markers would be elevated in the inflammopathic and coagulopathic groups compared to the adaptive group. METHOD(S): We prospectively enrolled and obtained blood from 130 inpatients with COVID19-related sepsis. Severity was classified by NIH ordinal scale. Gene expression analysis was performed by Nanostring nCounter (Inflammatix). Inflammatory proteins interleukin (IL)-6, IL8, IL10, IL1RA, IL1RL1, and IFNg and vascular markers ANGPT2, sICAM, vWF, ADAMTS13, and protein C were measured with OLINK proximity extension assay. Clinical variables were compared by chi-square and protein levels were compared using ANOVA with Bonferroni adjustment. RESULT(S): The transcriptomic classifier identified 32% (41) inflammopathic, 50% (65) adaptive and 18% (24) coagulopathic subjects. The inflammopathic group had more patients requiring mechanical ventilation (39% vs 9% vs 21%;p < 0.001) and higher 90-day mortality (32% vs 8% vs 13%, p = 0.016). Inflammatory cytokines IL8 and IL10 were significantly higher in inflammopathic compared to adaptive (p=0.038 and p=0.017 respectively), but not compared to coagulopathic (p>0.99 and p=0.24, respectively). Both the inflammopathic and coagulopathic groups expressed higher IL1RL1 and interferon-gamma compared to adaptive (IL1RL1;p< 0.001, p=0.002, IFNg;p=0.007, p=0.001). Plasma IL6 and IL1RA did not differ between groups, nor did many vascular proteins. The inflammopathic group expressed higher sICAM (p=0.049 vs adaptive) and lower ADAMTS13 compared to the adaptive group, and the coagulopathic group did not differ in its vascular protein expression. CONCLUSION(S): Transcriptomic subphenotypes are present in COVID-19 sepsis at similar proportions to non-COVID-19 sepsis. Inflammopathic subjects manifested higher severity of illness at admission, higher expression of inflammatory proteins and higher mortality. Markers of vascular injury did not distinguish the coagulopathic group. Integrating RNA and protein expression may offer new insights to host immune dysregulation during COVID sepsis.
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.