Revealing Common Mechanisms of Mortality in Severe COVID-19 and Sepsis Patients

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As of July 2023, the world has been grappling with the COVID-19 pandemic, which has infected over 650 million people and claimed the lives of 6-18 million individuals worldwide.

The severity of this disease has been particularly evident among those patients admitted to the intensive care unit (ICU), who face staggeringly high mortality rates, with up to 32% succumbing to the virus. The primary cause of death among these patients is multiple organ failure, reflecting a striking resemblance to severe sepsis.

Sepsis, a life-threatening condition marked by organ failure, is traditionally associated with a dysregulated host response to infection, most commonly bacterial but also viral and fungal in origin. It is estimated that sepsis claims the lives of 11 million people annually and plays a role in 1 in 5 global deaths.

In regions like North America, Europe, and Australia, the 30-day mortality rates for sepsis and septic shock stand at 24.4% and 34.7%, respectively, and these numbers are even higher in lower and middle-income countries. Given the parallels 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.

Recent research has demonstrated that sepsis endotypes can effectively classify COVID-19 patients based on the severity of their condition, highlighting the shared mechanisms between these two conditions. This research also suggests that severe COVID-19 and non-COVID-19 sepsis patients exhibit transcriptionally indistinguishable mechanisms after a week in the ICU.

Despite the high mortality rates associated with sepsis, there is currently no specific treatment available beyond antibiotics and supportive management, such as fluid resuscitation. Decades of clinical trials have been conducted in an effort to develop effective sepsis treatments, but they primarily focused on the inflammatory aspects of the condition.

It has become evident that a concurrent immunosuppressive component exists in sepsis, potentially serving to mitigate life-threatening inflammation. Consequently, using immunosuppressive or anti-inflammatory therapies can inadvertently worsen immune dysregulation and expose patients to lethal opportunistic pathogens.

This dual process of immunosuppression and inflammation is part of a syndrome referred to as “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS).

It is believed to occur in septic ICU patients and results in recurrent nosocomial infections, poor wound healing, an inability to self-care, and ultimately, death. However, the mechanistic underpinnings of why patients progress to death in sepsis have not been fully defined. Previous research identified five sepsis endotypes, two of which were correlated with higher mortality rates.

In addition to genetic biomarkers, various blood biomarkers have been shown to predict disease severity and mortality in COVID-19. These include C-reactive protein, procalcitonin, D-dimer, interleukin-6, lactate dehydrogenase, ferritin, plasma Gas6, lymphopenia, and thrombocytopenia, many of which have also been investigated in sepsis.

The treatment of COVID-19 has seen unprecedented scientific interest and funding, resulting in successful clinical trials that have uncovered effective therapies. Immunomodulators such as corticosteroids, tocilizumab, and baricitinib have shown promise in reducing mortality and disease severity.

Given the potential shared mortality mechanisms between COVID-19 and sepsis patients, these promising results hold significant implications for sepsis therapeutics. Both conditions are highly dynamic, necessitating analysis of multiple time points to fully understand disease trajectories and uncover additional pathophysiology that cannot be discerned from a single time point.

In this study, our aim was to identify shared mechanistic trajectories related to mortality in severe COVID-19 patients and contemporaneous non-COVID-19 sepsis patients. We hypothesized that shared gene expression changes over time could shed light on common mechanisms of injury and repair, with broad therapeutic implications.

Our findings revealed that persistent immune dysfunction was strongly associated with mortality in both SARS-CoV-2-positive and negative patients, a discovery that was validated in other public datasets of COVID-19 and sepsis patients.

Moreover, based on this persistence of immune dysfunction, we identified potential treatments that could target these genes in both COVID-19 and non-COVID-19 sepsis.

Shared Mechanistic Trajectories in Severe COVID-19 and Sepsis

Our study sought to unravel the intricate connections between severe COVID-19 and sepsis by examining the gene expression changes over time in patients suffering from these conditions. This research aimed to identify common mechanisms that contribute to mortality, which could pave the way for more effective treatments.

Immune Dysfunction as a Key Player

One of the standout findings of our study was the strong association between persistent immune dysfunction and mortality, regardless of whether the patients were infected with SARS-CoV-2 or not. This suggests that while the origin of the infection may differ, the immune response and its dysfunction in severe COVID-19 and sepsis share commonalities.

The identification of this persistent immune dysfunction highlights a crucial target for therapeutic interventions. By understanding and targeting the genes and pathways responsible for this dysfunction, we may be able to develop treatments that can mitigate the severity and mortality of both conditions. This discovery has the potential to transform the landscape of severe COVID-19 and sepsis treatment, offering new hope to patients and healthcare providers.

Validation Across Public Datasets

To ensure the robustness and validity of our findings, we extended our analysis to other publicly available datasets containing information on both COVID-19 and sepsis patients. The consistent presence of persistent immune dysfunction as a predictor of mortality in these datasets reinforces the significance of our discovery.

These results are not limited to a specific cohort or dataset but appear to be a consistent feature of severe COVID-19 and sepsis. This reaffirms the importance of immune dysfunction as a therapeutic target and provides a strong foundation for further research and clinical trials.

Potential Treatments for COVID-19 and Sepsis

Armed with the knowledge of persistent immune dysfunction as a common thread in severe COVID-19 and sepsis, we can begin to explore potential treatment options. Targeting the genes and pathways responsible for this dysfunction could lead to innovative therapies that have broad applications in both conditions.

The success of immunomodulators in treating severe COVID-19 patients suggests that these treatments may also hold promise for sepsis. Corticosteroids, tocilizumab, and baricitinib have demonstrated their ability to reduce mortality and disease severity in COVID-19 patients. These treatments could be adapted for use in sepsis, potentially offering a lifeline to those suffering from this life-threatening condition.

Discussion

In our investigation, we delved into the longitudinal analysis of severe COVID-19 and non-COVID-19 sepsis patients to uncover key insights into the shared mechanisms of mortality. The examination of gene expression data revealed a significant finding: persistent immune dysfunction in patients who eventually succumbed to their illnesses, while survivors exhibited partial immune resolution. Importantly, this phenomenon was consistent across patients regardless of their COVID-19 status, suggesting that shared mechanisms underlie these life-threatening conditions.

The persistent immune dysfunction we identified had both inflammatory and immunosuppressive components. This observation was not limited to the cohort under study; it was replicated in external datasets of COVID-19 and sepsis patients, providing robust evidence for its consistency across diverse populations. The connection between the persistence of immune dysfunction and mortality was further validated by the sustained enrichment of our previously published mortality signature and the results from endotype analysis.

The persistently dysregulated inflammatory processes we observed included key components such as IL-1, IL-6, TNFα, and the complement system, which failed to resolve in patients who ultimately did not survive. Notably, IL-4 and IL-13 signaling, indicative of a potential transition toward Type-2 immunity, was persistently upregulated in non-survivors. This shift could reflect increased pathogen burden and is associated with poor outcomes in sepsis. It may also signify cellular reprogramming, where innate immune cells lose their ability to respond effectively to pathogens, which can be highly detrimental during an infection. This is the first study to suggest that this persistent gene expression pattern, analogous to PICS, occurs similarly in both sepsis and severe COVID-19 ICU patients with worse outcomes.

While it remains uncertain what enables some patients to correct their immune dysfunction, individual factors like natural immunity, predisposing conditions, and underlying patient genetics could play a role. The idea of persistence also aligns with epigenetic mechanisms, as several immune genes were found among both persistent genes and differentially methylated genes in sepsis and COVID-19. Since non-survivors exhibited persistently dysregulated pathways that resolved in survivors, it suggests that there may be treatable traits and pharmacological methods capable of reversing this persistence and reducing mortality.

Several currently-approved and experimental immunomodulatory therapies for COVID-19 have shown promise, such as dexamethasone, IL-6 signaling inhibitors like tocilizumab and baricitinib, the IL-1 receptor antagonist anakinra, and the complement inhibitor vilobelimab. These therapies target enriched pathways and gene sets that were persistently dysregulated in non-survivors. Hence, targeting these persistent genes and mechanisms may present a valid approach to identify additional therapies. The inclusion of dexamethasone, a known effective treatment for COVID-19 and subsets of septic shock, further underscores the validity of these methods for identifying potential repurposed drugs for sepsis and COVID-19.

Additional potential immunomodulators that could address persistent inflammation include aspirin, sulfasalazine, and cyclosporine. Furthermore, other drugs without obvious immunomodulatory functions, such as thioridazine and flecainide, have demonstrated survival benefits in animal models of sepsis, likely through off-target inhibition of the NF-κB pathway. These identified drugs warrant further evaluation through in vitro, in vivo, and clinical trials to assess their potential efficacy.

Beyond addressing inflammatory mechanisms, it is equally crucial to tackle the adaptive immune deficits observed in this cohort. Treatments designed to restore adaptive suppression, focusing on T-cell functions and numbers, should be considered. These therapies might be administered concurrently with anti-inflammatory approaches or selectively applied to patients based on their underlying gene expression profiles or clinical variables.

Some potential treatments targeting adaptive immune suppression include checkpoint inhibitors and IL-7, which are currently under evaluation for sepsis and should also be considered for severe COVID-19. The inclusion of IL7R as one of the top downregulated hub genes further supports the potential use of IL-7. Monitoring immune function longitudinally throughout hospitalization, such as using gene expression panels and cytokine measurements, can identify patients who fail to resolve immune dysfunction within the first week of ICU admission, guiding healthcare providers to consider additional care or enrollment in immunomodulatory clinical trials. The timing of treatment in relation to the patient’s disease timeline is a critical consideration, as demonstrated by this cohort.

However, this study is not without its limitations. The results are primarily derived from a single cohort of predominantly male patients, and while the central finding of persistence has been corroborated by re-analysis of other studies, further validation in larger, sex-balanced cohorts is necessary. Despite the modest sample size, the study was adequately powered to identify thousands of differentially expressed genes, indicating its robustness. Various potential confounders, including corticosteroid use, COVID-19 status, and sample imbalance, were addressed and did not substantially affect the gene expression patterns observed.

In summary, our research has revealed that mortality in both sepsis and COVID-19 is closely associated with persistent immune dysfunction during the first week in the ICU, encompassing both inflammatory and immunosuppressive components. To improve patient outcomes, novel immunomodulatory treatments should aim to address immune dysfunction throughout the ICU stay. We have identified multiple immunomodulatory drug candidates, which should undergo further evaluation to determine their efficacy in vitro, in vivo, and in clinical trials. This comprehensive approach that targets persistent inflammation and adaptive immune deficits offers new hope for patients suffering from these life-threatening conditions.

Conclusion

The COVID-19 pandemic and sepsis represent two significant global health challenges, each with their own unique characteristics and complexities. However, our research has unveiled a compelling connection between these two conditions in the form of persistent immune dysfunction as a predictor of mortality.

This breakthrough offers a fresh perspective on the treatment of severe COVID-19 and sepsis. By identifying shared mechanistic trajectories, we can potentially develop targeted therapies that not only mitigate the impact of the pandemic but also transform the outlook for sepsis.


reference link : https://www.frontiersin.org/articles/10.3389/fimmu.2023.1254873/full

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