A. The traditionally accepted SIRS-CARS phenomenon holds that mortality from severe sepsis and injury is a consequence of an overabundant and dysregulated early innate immune response from the over production of proinflammatory mediators and cytokines, leading to endothelial injury, tissue damage, inadequate perfusion and MOF, ultimately leading to death. In patients who survive this early SIRS event, a compensatory anti-inflammatory responses (CARS) including suppression of adaptive immunity results. Additional insults such as nosocomial infection can cause a late “second-hit” that may lead to recurrent SIRS. B. Recently, the Glue Grant showed that based on leukocyte genomic expression patterns, there is a simultaneous induction of innate (both pro- and anti-inflammatory genes) and suppression of adaptive immunity genes, and that there is minimal genomic or clinical evidence for a “second-hit” phenomenon. Reprinted with permission from Journal of Experimental Medicine19.