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KEY POINTS

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  • Current paradigms of sepsis include both pro- and anti-inflammatory pathway activation to different degrees and at different phases of the syndrome.

  • Failure to recognize and understand the dynamic changes in immune response in sepsis may in part explain the failure of a number of anti-inflammatory drugs and biologics studied in critically ill patients.

  • The anti-inflammatory or immunosuppressed state associated with sepsis and other forms of critical illness is often protracted and places patients at risk for complicating nosocomial infections and activation of latent infections.

  • When clinically significant, the anti-inflammatory state associated with sepsis is termed immunoparesis or immunoparalysis.

  • Cell and humoral biomarkers are needed to properly characterize the individual patient’s immune status to guide targeted and personalized therapy to modulate both excessive immune stimulation as well as immune suppression.

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INTRODUCTION

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HISTORY—DEFINITION
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Sepsis [σήψις] is the original Greek word for the “decomposition of animal or vegetable organic matter in the presence of bacteria.” The word is found for the first time in Homer’s poems, where Sepsis is a derivative of the verb form sepo [σήπω], which means “I rot.” The term sepsis is also found in the Corpus Hippocraticum exchangeably with the word sepidon [σηπεδών] (“the decay of webs”): Epidemic. B. 2,2, Prorret. I. 99. Aristoteles, Plutarch, and Galen use the word sepsis [σηψις] in the same meaning as Hippocrates.1

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This original meaning connoted decay and wound putrefaction and described a process of decomposition of organic matter and tissue breakdown resulting in disease (foul odor, pus formation, dead tissue) and eventually to death.2 Thus, the word sepsis has persisted for 2700 years with more or less unchanged meaning. Subsequent works just confirmed the causal link between microbes and suppurative infections or systemic symptoms and clinical findings from infections establishing the infections as the underlying disease. Hugo Schottmuller in 1914 founded the modern definition of sepsis and was the first to describe that the presence of an infection was a fundamental component of the disease.3

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In 1972, Lewis Thomas described sepsis in the following way: “It is our response to [the microorganism’s] presence that makes the disease. Our arsenals for fighting off bacteria are so powerful … that we are more in danger from them than the invaders.” and popularizing the theory that “…it is the [host] response … that makes the disease.”4 Finally, the concept entered into daily clinical practice when Roger Bone and colleagues defined sepsis as a systemic inflammatory response syndrome that can occur during infection.5

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In recent years this syndromic characterization of sepsis has been expanded to SIRS (systemic inflammatory response syndrome), CARS (compensatory anti-inflammatory response syndrome), and MARS (mixed antagonists response syndrome), with recognition that immune dysfunction during sepsis may be a significant aspect of pathogenesis.6,7

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Currently sepsis is considered a host immune response to ...

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