“Defining” Sepsis: Moving Toward Measuring the “Dysregulated Host Response”*

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In 1991, a joint Society of Critical Care Medicine (SCCM)/American College of Chest Physicians task force set out to provide a set of uniform criteria by which patients with sepsis might be recognized (1). These criteria remained largely unchanged until February of 2016. At that time, a joint SCCM/European Society of Intensive Care Medicine task force developed and published new definitions of sepsis and clinical criteria to identify patients likely to have this common and deadly disorder (sepsis-3) (2–4). In the interim, changes in management that prolonged survival (5) coupled with an enhanced understanding of the pathobiology of the disorder had significantly altered conceptualization of sepsis. Thus, the task force refined the definition of sepsis to “life-threatening organ dysfunction caused by a dysregulated host response to infection” (4). Of particular importance in construction of this new definition was recognition that the immune status of septic patients was far more complex than initially envisioned. Specifically, septic patients exhibited characteristics of both a dramatically enhanced response to infection along with extensive immunosuppression (6, 7). The members of the task force recognized that this new definition was inadequate because it offered the clinician little that was of practical value. Therefore, the task force undertook to develop new criteria that could be used to clinically identify patients with infection who were likely to have or to develop sepsis. Further discussion of these new criteria (and, indeed, the controversy that has accompanied their release) is beyond the scope of this discussion. What is important is that the nature of the definition made the development of clinical criteria necessary. This imperative clearly delineated important areas for future investigation. Specifically, the next frontier in sepsis translational research is to attach clinical utility to the terms “organ dysfunction” and “dysregulated host response.”
In this issue of Critical Care Medicine, Hoogendijk et al (8) take what is perhaps the first step in this process. These investigators obtained blood samples from septic patients and examined activity in a number of different leukocyte subpopulations, seeking evidence of an immune state that differed from those of the healthy individuals whose samples serve as controls. The study was appropriately conducted, and although there are some issues regarding design, it is most important to discuss what these investigations can tell us about the “dysregulated host response.”
Hoogendijk et al (8) focused on two key inflammatory pathways; one involving cytoplasmic responses mediated by the mitogen-activated protein kinase p38 and the second the activation of several key transcriptional regulators collectively referred to as “nuclear factor kappa B” (NF-κB). Because p38 activity in study septic patients and controls did not differ appreciably, our discussion will focus solely on NF-κB.
NF-κB has been called the “master regulator of inflammation” (9). Although Hoogendijk et al (8) discuss some basic aspects of NF-κB biology (8), it is important to add additional details. The name NF-κB reflects the initial discovery of this mediator; in 1968, Sen and Baltimore (10) identified its role in the transcription of immunoglobulin κ-light chains in B-lymphocytes. The basic, active NF-κB molecule (Fig. 1) is a dimer composed of two of five species (11). Among these five, three—RelA (also called p65), RelB, and c-Rel—have a highly conserved immunoglobulin-like N-terminus that facilitates dimerization, DNA binding and interaction with other proteins, especially cytoplasmic inhibitor molecules. The carboxy-terminus, in turn, contains an element that confers transcriptional activity. In contrast, the other two molecules p50 and p52 each arise from the proteosomal degradation of a precursor (p105 and p100, respectively) and lack the domain that effects transcription (12).

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