Chasing the Ghost: Hyperinflammation Does Not Cause Sepsis.

Area of Science:

• Critical care medicine
• Infectious diseases
• Immunology
• Medical research methodology

Background:

• Sepsis, a life-threatening organ dysfunction caused by infection, includes severe Coronavirus disease-2019 (COVID-19).
• The prevailing hypothesis posits that sepsis results from excessive inflammation, termed a cytokine storm.
• Despite extensive research and numerous clinical trials, anti-inflammatory strategies have not reduced sepsis mortality.

Purpose of the Study:

• To critically examine the theoretical underpinnings of the hyperinflammation or cytokine storm hypothesis of sepsis.
• To evaluate the scientific validity and cause-and-effect relationship between hyperinflammation and sepsis.
• To assess the implications of this paradigm for sepsis and COVID-19 treatment strategies.

Main Methods:

• Theoretical analysis of the scientific literature supporting the hyperinflammation concept in sepsis.
• Review of evidence from laboratory studies and clinical trials investigating anti-inflammatory approaches.
• Conceptual analysis using Thomas Kuhn's framework of scientific paradigms to understand concept persistence.

Main Results:

• The analysis reveals significant conceptual weaknesses and a lack of established causality between hyperinflammation and sepsis.
• Decades of research and over 100 clinical trials targeting inflammation have failed to improve sepsis survival rates.
• The cytokine storm concept demonstrates remarkable resilience, exhibiting characteristics of an unfalsifiable scientific paradigm.

Conclusions:

• Anti-inflammatory approaches to sepsis therapy are unlikely to succeed due to fundamental flaws in the underlying hypothesis.
• Applying the hyperinflammation paradigm to COVID-19 treatment is also at high risk of failure.
• Rejection of the cytokine storm concept as the cause of sepsis is called for, redirecting resources to more promising research avenues.