RNAemia and Severe Coronavirus Disease 2019: Candidate Treatment Targets Identified Through Transcriptomics
Year: 2026
Type: article
Study design: Observational Study
Abstract: INTRODUCTION: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.
Authors: Sultanah Alharthi, Nusrat J Epsi, David A Lindholm, Pavol Genzor, Milissa Jones, Heba H Mostafa, Anuradha Ganesan, Rupal Mody, Katrin Mende, Manish Bhomia, Carlos Maldonado, Timothy Burgess, David Tribble, Mark P Simons, Rhonda E Colombo, Stephanie A Richard, Brian K Agan, Clifton L Dalgard, John S Dumler, Simon D Pollett, Paul W Blair, J Cowden, M Darling, S DeLeon, A Markelz, S Merritt, T Merritt, N Turner, T Wellington, S Bazan, P K Love, N Dimascio-Johnson, N Elnahas, E Ewers, K Gallagher, C Glinn, U Jarral, D Jennings, D Larson, K Reterstoff, A Rutt, A Silva, C West, J Bowman, S Chambers, C Colombo, C Conlon, K Everson, P Faestel, T Ferguson, L Gordon, S Grogan, S Lis, M Martin, C Mount, D Musfeldt, D Odineal, M Perreault, W Robb-McGrath, R Sainato, C Schofield, C Skinner, M Stein, M Switzer, M Timlin, S Wood, S Banks, R Carpenter, L Kim, K Kronmann, T Lalani, T Lee, A Smith, R Smith, R Tant, T Warkentien, C Berjohn, S Cammarata, N Kirkland, D Libraty, R Maves, G Utz, C Bradley, S Chi, R Flanagan, A Fuentes, M Jones, N Leslie, C Lucas, C Madar, K Miyasato, C Uyehara, H Adams, B Agan, L Andronescu, A Austin, B Barton, D Becher, C Broder, C Byrne, K Chung, J Davies, C English, N Epsi, C Fox, M Fritschlanski, A Hadley, P Hickey, E Laing, C Lanteri, J Livezey, A Malloy, A Michel, R Mohammed, C Morales, P Nwachukwu, C Olsen, E Parmelee, J Rothenberg, J Rozman, J Rusiecki, D Saunders, E Samuels, M Sanchez, A Scher, M Simons, A Snow, K Telu, M Tso, L Ulomi, M Wayman, N Hockenbury, J Rothenberg, T Chao, R Chapleau, M Christian, A Fries, C Harrington, V Hogan, S Huntsberger, K Lanter, E Macias, J Meyer, S Purves, K Reynolds, J Rodriguez, C Starr, J Iskander, I Kamara, B Barton, D Hostler, J Hostler, K Lago, J Mehrer, T Hunter, J Mejia, J Montes, R Resendez, P Sandoval, I Barahona, A Baya, N Huprikar, B Johnson, S Peel
Institutions: Henry M. Jackson Foundation, Vanderbilt University Medical Center, Uniformed Services University of the Health Sciences, Brooke Army Medical Center, Joint Base San Antonio, Johns Hopkins University, Johns Hopkins Medicine, Walter Reed National Military Medical Center, William Beaumont Army Medical Center, Womack Army Medical Center, Madigan Army Medical Center
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,763
Awards: G1381013786, G5476414851
OpenAlex ID: W7171730982