RNAemia and Severe COVID-19: Candidate Treatment Targets Identified Through Transcriptomics

The presence of SARS-CoV-2 RNA in blood has been proposed as a marker of severe COVID-19, but it is unclear whether RNAemia mediates the pathway toward worsening disease. We hypothesized that RNAemia is associated with severe disease and distinct gene expression patterns are associated with RNAemia and severe COVID-19. These RNAemia-associated patterns may identify COVID-19 treatment targets.

We analyzed 202 hospitalized COVID-19 participants from a multi-center U.S. Military Health System cohort using digital droplet PCR (ddPCR) to quantify SARS-CoV-2 RNA in plasma and performed host RNA sequencing of peripheral blood. Differential gene expression (DGE) logistic regression models were used to assess associations among RNAemia, host gene expression, and disease severity.

RNAemia was detected in 39.1% of participants and was associated with severe disease (54% vs. 32% in RNAemia-negative participants; p <0.001). In final adjusted models, independent predictors of severity included RNAemia (adjusted Odds Ratio [aOR] range 1.99-2.24, all p ≤ 0.04), as well as host genes ADAMTS2 (aOR = 1.58, p < 0.001), OLAH (aOR = 1.55, p < 0.001), and PCSK9 (aOR = 1.60, p < 0.001).

RNAemia is an independent predictor of COVID-19 severity. However, host gene expression changes associated with RNAemia, particularly involving OLAH, PCSK9, and ADAMTS2, had stronger statistical evidence of severe outcomes than RNAemia itself. PCSK9 is an intervenable treatment target worth further study.