Longitudinal Single Cell Atlas of COVID-19 Identifies an Early, Transient Prognostic Signature

Although the majority of COVID-19 patients are asymptomatic or mildly symptomatic at diagnosis, some will subsequently progress to pneumonia, oxygen desaturation and other symptoms requiring active clinical management. However, molecular markers that identify high-risk patients early in the disease course (Days 1-8 from symptom onset) are scarce, due to the paucity of relevant longitudinal studies. We performed longitudinal single cell RNA-seq on 286 peripheral blood samples from 108 COVID-19 patients, 73 of which had at least one early sample. By examining discrete cell subtypes as well as continuous single cell states, we identified upregulation of type I IFN response genes as the predominant cellular prognostic signature of future disease severity. Type I IFN response was dynamic and complex, spiking early in progressors and then regressing to the cohort mean at the very next sampling, with the cohort mean itself receding to asymptomatic levels by Day 14 regardless of severity. Moreover, in severe and critical cases, IFN response was impaired during Days 5-8, partially due to upregulation of SOCS3 and other negative regulators. We have identified an early prognostic signature for predicting COVID-19 severity as well as potential mechanisms underlying the dysfunctional host immune response in severe disease.EGA study EGAS00001005545