It has been four years since the start of the COVID-19 pandemic, with over 700 million infections and 7 million deaths. These numbers continue to rise as this disease significantly impacts our healthcare system and society, warranting continued extensive research. Two recent studies by the Hancock Lab^1,2, published in Frontiers in Immunology, focus on severe COVID-19 and another infectious disease called sepsis, revealing surprising parallels in their pathophysiology and offering potential new treatments for both diseases. The authors investigated 42 patients admitted to the intensive care unit (ICU) at St. Michael’s Hospital in Toronto for respiratory complications, either from severe COVID-19 or pulmonary sepsis, and followed up a week later. Whole blood was drawn at both timepoints, allowing for longitudinal study of gene expression.

Displayed is a protein-protein interaction network of dysregulated persistent genes found in COVID-19 and sepsis patients who died in the ICU [2]. Circled are the top 15 hub genes, which are genes and their protein products with multiple interactions with other dysregulated genes/proteins during severe disease. Hub genes are attractive pharmacological targets for drugs as their protein products may be key in driving underlying pathology, and the authors found several repurposed drugs that may target these hubs to treat both diseases [2].

The first study¹, “Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms” explores how the gene expression profile of COVID-19, a novel disease caused by a novel virus, is surprisingly similar to sepsis, a disease that has been studied since the time of Hippocrates. Sepsis is a severe condition that occurs when the body’s response to infection goes into overdrive and causes organ damage, and is estimated to be involved in 1 of 5 global deaths. At ICU admission, COVID-19 patients and sepsis patients had similar clinical presentation; however, they had over 1,000 genes that were differentially expressed between them. Many antiviral genes were expressed higher in COVID-19 patients, which was expected considering the viral etiology of COVID-19. Surprisingly, when these two groups of patients were compared one week later, the number of differentially expressed genes dropped dramatically to only 9 genes, suggesting a convergence in gene expression indicative of an ultimate shared pathophysiology. Furthermore, throughout the hospitalization, both groups had similar immune dysfunction, with dysregulation of immune pathways such as interleukin-1 and interleukin-6 signaling, complement pathways, and neutrophil degranulation.

The authors concluded that due to these gene expression similarities, severe COVID-19 was essentially a form of viral sepsis, with a distinct initial antiviral response on top of shared immune dysfunction. This finding has two important clinical implications. First, the early peak and waning of the antiviral response likely explains why antiviral therapies for COVID-19 (e.g., remdesivir, Paxlovid, and monoclonal antibodies against viral proteins) are most effective early in disease, when the major driver of disease is the virus itself. Once this antiviral response passes, especially in later, more severe forms of this disease, the focus should shift to targeted immunomodulatory therapies to treat underlying immune dysfunction. Second, considering that COVID-19 is a form of viral sepsis, this further supports the application of decades of sepsis research into biomarkers and clinical care to COVID-19. Likewise, the vast amount of research into new immunomodulatory therapies developed for COVID-19 may be repurposed and tested in sepsis patients. This reciprocity would be extremely beneficial as sepsis currently lacks specific treatments beyond antibiotics and supportive care.

What immunomodulatory therapies would be appropriate for both COVID-19 and sepsis? To answer this question, further investigations regarding the shared immune dysfunction was necessary. This was done in the second study², “Persistence is Key: Unresolved Immune Dysfunction is Lethal in Both COVID-19 and non-COVID-19 Sepsis”, which focuses on the mechanisms driving mortality in both groups. Interestingly, patients who eventually died in the ICU had almost a 4-fold higher number of “persistent genes” compared to survivors. Persistent genes were genes that remained dysregulated throughout the ICU stay, and many of these genes played a key role in several immune pathways, highlighting persistent immune dysfunction. This was centred around both adaptive immunosuppression (e.g., dysfunctional T cell signaling) and innate immune overactivation (e.g., IL-1 signaling). To find potential therapeutics to target these pathways, the authors turned to bioinformatic methods such as drug-gene set enrichment and network analysis to find already approved drugs that could be repurposed to inhibit some of these persistently dysregulated genes. Drug-gene set enrichment focused on identifying drugs that could turn off specific groups of genes, while network analysis identified “hub” genes that interact with multiple other dysregulated genes and could be pharmaceutically targeted to inhibit whole processes. Overall, several repurposed drugs were identified that could be investigated further in in vitro, in vivo, and clinical studies.

The results from both studies highlight the importance of understanding the immune dysregulation seen in COVID-19, which could guide clinical management and opens doors to novel treatment strategies for both COVID-19 and for sepsis. As we continue to grapple with more iterations of SARS-CoV-2, these insights are vital for managing COVID-19 and ultimately preparing for future pandemics.

Link to the papers:

• https://www.frontiersin.org/articles/10.3389/fimmu.2023.1167917/full
• https://www.frontiersin.org/articles/10.3389/fimmu.2023.1254873/full
  • Authors: Andy An, Arjun Baghela, Peter Zhang, Reza Falsafi, Amy Lee, Uriel Trahtemberg, Andrew Baker, Claudia dos Santos, Robert Hancock

References:

• An AY, Baghela A, Zhang P, Falsafi R, Lee AH, Trahtemberg U, Baker AJ, dos Santos CC, Hancock REW. Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms. Frontiers in Immunology 2023; 14:1167917.
• An AY, Baghela A, Zhang P, Falsafi R, Lee AH, Trahtemberg U, Baker AJ, dos Santos CC, Hancock REW. Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis. Frontiers in Immunology 2023; 14:1254873.