The University of British Columbia, Simon Fraser University, and St. Michael’s Hospital at the University of Toronto have conducted a study investigating the genetic basis of severe COVID-19 and sepsis, two conditions that have posed significant challenges in the healthcare system, particularly in the ICU. The researchers aimed to understand the persistent immune dysfunction seen in these conditions and identify potential therapeutic interventions.
The study revealed that sepsis involves both inflammation and immunosuppression, leading to an imbalance that contributes to poor outcomes. This understanding has been termed “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS), a condition associated with severe sepsis and eventual death.
To uncover the mechanistic pathways leading to mortality in severe COVID-19 and sepsis, the researchers analyzed whole blood samples from ICU patients at two timepoints. They found that non-survivors, regardless of COVID-19 status, had a higher number of persistent genes that remained dysregulated throughout the first week of ICU admission. These genes were associated with immune-related pathways and were validated in external datasets of COVID-19 and sepsis patients.
The study also identified several immune-related genes that were persistently dysregulated in non-survivors, including PCSK9, CACNA2D2, IL10RB, TYK2, and ICAM1. These genes were associated with worse outcomes in both COVID-19 and sepsis patients.
Pathway analysis showed that persistently upregulated pathways in non-survivors were related to interleukin (IL) and inflammatory signaling, indicating ongoing inflammation and unresolved immune dysfunction. On the other hand, adaptive immune activation pathways were persistently downregulated, reflecting sustained immunosuppression.
The researchers also identified two endotypes, Neutrophilic-Suppressive (NPS) and Inflammatory (INF), associated with worse outcomes in both sepsis and COVID-19 patients. Furthermore, a 38-gene mortality signature derived from early sepsis patients was consistently enriched in non-survivors, further highlighting the link between immune dysfunction and mortality.
Recognizing the crucial role of immune dysfunction, the study explored potential therapeutic interventions. Using two systems-biology approaches, the researchers identified drugs that could target the persistent genes and immune pathways seen in non-survivors. These included anti-inflammatory drugs, corticosteroids, and other medications such as antipsychotics and anti-arrhythmics. Repurposed drugs like tocilizumab, baricitinib, and omeprazole also showed promise in mitigating immune dysfunction.
In conclusion, this study sheds light on the shared immune dysfunction in severe COVID-19 and sepsis, emphasizing the need for timely interventions to restore immune balance. The findings offer potential therapeutic strategies and repurposed drug candidates, which could ultimately improve the prognosis and reduce mortality rates in these devastating conditions.