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

Abstract

IntroductionSevere 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).MethodsIn 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.ResultsAt 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.DiscussionEarly 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.

Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis

“…This persistent immune dysfunction involved both inflammatory and immunosuppressive components ( Figures 1C , 2 , 3A ), as observed in both COVID-19 and non-COVID-19 sepsis non-survivors ( Figure S2C, D ) and in external datasets of COVID-19 and sepsis patients ( Figure S4 ). While differences in the early antiviral response existed between these two groups ( Figures S2B, S9 ), consistent with our previous work ( 11 ), overall, the underlying persistent immune dysfunction involved in mortality was highly conserved in both COVID-19 and non-COVID-19 sepsis ( Figure S2D ). The connection between persistence and mortality was further supported by persistent enrichment of our published mortality signature ( Figure 4A ) and the results from the endotype analysis, where most non-survivors remained associated with the high severity endotypes NPS and INF throughout disease ( Figure 4C ).…”

“…Whole blood from 5 healthy controls from Vancouver, Canada were processed alongside the patient samples. Further details on study design and RNA-Seq methodology can be found in our previously published protocol ( 11 ).…”

“…Due to similarities in immune dysfunction, endothelial disruption, cytokine levels, gene expression, and long-term consequences, there is a growing consensus that severe COVID-19 should be classified and treated as a form of viral-associated sepsis ( 8 ). We recently have shown that our sepsis endotypes can accurately classify COVID-19 patients based on severity ( 9 , 10 ) and that contemporaneous severe COVID-19 and non-COVID-19 sepsis patients converge into transcriptionally indistinguishable mechanisms after a week in the ICU ( 11 ).…”

“…If mortality mechanisms are shared between COVID-19 and sepsis patients, these promising results will likely have applications to sepsis therapeutics. Nevertheless, both sepsis and COVID-19 are highly dynamic diseases ( 11 , 14 , 24 ), requiring analysis of multiple timepoints to fully understand disease trajectories and uncover additional pathophysiology that cannot be detected from a single timepoint.…”

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

“…The down-regulation of these immune pathways suggested a decrease in the activity of multiple inflammatory processes, which was further supported by the upregulation over time of the anti-inflammatory pathway “Interleukin-10 signaling” ( Figure 1C ). In particular, these hemostasis and inflammatory pathways have been shown in the literature to be largely upregulated in hospitalised COVID-19 patients ( 50 – 52 ). Thus, the observed down-regulation over time may suggest a return to homeostasis after discharge in only patients who did not have post-COVID symptoms at follow-up.…”