Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms.

Introduction: Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features. To what extent they share mechanistically-based gene expression trajectories throughout hospitalization was unknown. Our objective was to compare gene expression trajectories between severe COVID-19 patients and contemporaneous non-COVID-19 severe sepsis patients in the intensive care unit (ICU). Methods: In this prospective single-center observational cohort study, whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Results: At ICU admission, despite COVID-19 patients being almost clinically indistinguishable from non-COVID-19 sepsis patients, COVID-19 patients had 1,215 differentially expressed genes compared to non-COVID-19 sepsis patients. After one week in the ICU, the number of differentially expressed genes dropped to just 9 genes. This drop coincided with decreased expression of antiviral genes and relatively increased expression of heme metabolism genes over time in COVID-19 patients, eventually reaching expression levels seen in non-COVID-19 sepsis patients. Both groups also had similar underlying immune dysfunction, with upregulation of immune processes such as "Interleukin-1 signaling" and "Interleukin-6/JAK/STAT3 signaling" throughout disease compared to healthy controls. Discussion: Early on, COVID-19 patients had elevated antiviral responses and suppressed heme metabolism processes compared to non-COVID-19 severe sepsis patients, although both had similar underlying immune dysfunction. However, after one week in the ICU, these diseases became indistinguishable on a gene expression level. These findings highlight the importance of early antiviral treatment for COVID-19, the potential for heme-related therapeutics, and consideration of immunomodulatory therapies for both diseases to treat shared immune dysfunction.