Preventing Mortality in COVID-19 Patients: Which Cytokine to Target in a Raging Storm?

Area of Science:

• Immunology
• Virology
• Critical Care Medicine

Background:

• Severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, leads to significant global morbidity and mortality.
• A hyperinflammatory cytokine storm is a major driver of mortality in severe/critical COVID-19 patients.
• The specific inflammatory mediator initiating fatal COVID-19 outcomes remains undefined, hindering targeted therapeutic development.

Purpose of the Study:

• To propose a three-stage immunopathological model for COVID-19 mortality.
• To guide therapeutic strategies by defining distinct clinical features of each stage.
• To critically evaluate the efficacy of targeting inflammatory cytokines/chemokines in COVID-19.

Main Methods:

• Review and interpretation of recently published clinical trial data on COVID-19 patient treatments.
• Analysis of immunopathological pathways contributing to COVID-19 mortality.
• Discussion of factors influencing the selection of cytokine/chemokine targets, treatment timing, and combination therapies.

Main Results:

• The immunopathological pathway leading to COVID-19 mortality can be segmented into three distinct clinical stages.
• Clinical efficacy of IL-1 blockade in preventing COVID-19 mortality is associated with significant caveats.
• IL-6 blockade demonstrates suboptimal efficacy in preventing COVID-19 mortality.

Conclusions:

• A staged approach to understanding COVID-19 immunopathology can inform therapeutic strategies.
• Current evidence suggests limitations in the effectiveness of IL-1 and IL-6 blockade for preventing COVID-19 mortality.
• Identifying optimal inflammatory targets, treatment timing, and combinations is crucial for improving outcomes in severe COVID-19.