Coronavirus disease 2019 (COVIDâ19) caused by severe acute respiratory syndrome coronavirus 2 (SARSâCoVâ2) infection can result in severe immune dysfunction, hospitalization, and death. Many patients also develop longâCOVIDâ19, experiencing symptoms months after infection. Although significant progress has been made in understanding the immune response to acute SARSâCoVâ2 infection, gaps remain in our knowledge of how innate immunity influences disease kinetics and severity. We hypothesized that cytometry by timeâofâflight analysis of PBMCs from healthy and infected subjects would identify novel cell surface markers and innate immune cell subsets associated with COVIDâ19 severity. In this pursuit, we identified monocyte and dendritic cell subsets that changed in frequency during acute SARSâCoVâ2 infection and correlated with clinical parameters of disease severity. Subsets of nonclassical monocytes decreased in frequency in hospitalized subjects, yet increased in the most severe patients and positively correlated with clinical values associated with worse disease severity. CD9, CD163, PDL1, and PDL2 expression significantly increased in hospitalized subjects, and CD9 and 6âSulfo LacNac emerged as the markers that best distinguished monocyte subsets amongst all subjects. CD9
+
monocytes remained elevated, whereas nonclassical monocytes remained decreased, in the blood of hospitalized subjects at 3â4 months postinfection. Finally, we found that CD9
+
monocytes functionally released more ILâ8 and MCPâ1 after LPS stimulation. This study identifies new monocyte subsets present in the blood of COVIDâ19 patients that correlate with disease severity, and links CD9
+
monocytes to COVIDâ19 progression.