The host response to sepsis

Sir William Osler, probably the most influential physician in the English-speaking world at the turn of the century more than a hundred years ago, wrote the following about sepsis in his famous text book, The Evolution of Modern Medicine (1904): Except on few occasions, the patient appears to die from the body's response to infection rather than from it. The assumption that sepsis is the consequence of an overwhelming inflammatory reaction of the patient to microorganisms was widely accepted for many years. Current knowledge indicates that this paradigm is oversimplified and only partially true. The original theory that sepsis mortality is caused by an overstimulated immune system was based on studies in animals that were infused with large doses of bacteria or bacterial products, in particular lipopolysaccharide (LPS), the toxic component of the Gram-negative bacterial cell wall. Such infusions result in a brisk systemic release of an array of pro-inflammatory mediators of which many have been found to be directly responsible for the death of the host. In a hallmark manuscript published in 1985, Beutler and colleagues reported that elimination of the early activity of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α, after intravenous injection of LPS prevented death in mice [1]. Two years later, these results were confirmed by Tracey and colleagues, who showed that a monoclonal anti-TNF-α antibody protected baboons against lethal Gram-negative sepsis [2].