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Background: Sepsis arises, by definition, from a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in antimicrobial treatments and organ support, pharmacological breakthroughs remain limited. The human endotoxin model serves as a bridge between animal models and human trials, simulating systemic inflammatory response syndrome (SIRS) and sepsis for evaluating potential therapies. 

The COVID-19 pandemic, driven by SARS-CoV-2, caused widespread morbidity and mortality. Patients with severe disease exhibited immune dysregulation, characterized by hyperinflammation and immune suppression. Given the similarity in immune dysregulation, insights from previous SARS outbreaks and sepsis research were applied to the SARS-CoV-2, emphasizing the need to balance immune suppression and infection-fighting capacity in both conditions.

Methods: Part one involved a human endotoxemia model, where endotoxin was administered to healthy volunteers, to simulate systemic inflammatory response syndrome (SIRS). Inhaled nitric oxide (iNO) and glucocorticoid (GC) co-administration was assessed for immune modulation based on previous results from a porcine model. 

Part two focused on COVID-19 patients in the PRONMED cohort with severe disease admitted to the ICU, investigating longitudinal immune cells and biomarker levels. In addition potential sex-based differences in inflammatory profiles were evaluated.

Results: In the human endotoxemia model, iNO/GC failed to modify the immune response, despite promising results in a porcine study. Differences in species-specific responses and endotoxin dosing likely contributed to these outcomes. 

Among COVID-19 patients, elevated pro-inflammatory cytokines (TNFα, IL-6, IL-8), neutrophil activation, marked lymphopenia with attenuated expressions of lymphokines receptors were observed. In addition a dynamic aberrant expression of CD-markers was observed on neutrophils. 

Men had an overall heightened immune response compared to women, except for cytokines for Th1 response, where no difference was found.

Conclusions: The failure of iNO/GC to replicate animal results highlights challenges in translating findings across species.

In COVID-19 patients, significant immune dysregulation was observed. Tailored interventions—with precise patient selection, optimized timing and dosing, and potential influences from sex hormones—are likely key to improving outcomes and minimizing harm in sepsis patients. Additionally, further research is crucial to better understand the role of neutrophils in the adaptive immune response.