Immunologic Dissonance: A Continuing Evolution in Our Understanding of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS)

Abstract

Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest. Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory anti-inflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.

Injury Enhances Resistance to Escherichia coli Infection by Boosting Innate Immune System Function

“…These opposing assumptions were based on clinical observations and on many years of experience by us as well as others studying the influence of injury on immune function in animal models (22). Much of this prior research supported the conclusion that major injury led to diminished resistance to infection due to the development of the compensatory anti-inflammatory response syndrome noted clinically in critically ill patients and also in relevant rodent models of serious injury (25)(26)(27). We had also come to accept the idea that severe injury induces an initial SIRS that likely represents an overshoot of an evolutionarily conserved innate immune reaction to tissue injury.…”

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

“…It is also apparent that septic insults initiate concurrent or sequential antiinflammatory cascades during the course of sepsis, which likely mitigates the extent of inflammation and tissue injury. This antiinflammatory response, referred to as compensatory antiinflammatory response syndrome (CARS), is also believed to contribute to the increased susceptibility of critically ill patients to secondary nosocomial infections, due in part to sepsis-induced leukocyte "immunoparalysis" (2,5,8,11,(32)(33)(34)(35)(36). Interestingly, mortality is higher in patients with sepsis who display evidence of monocyte deactivation (2).…”

A Trojan Horse in Intensive Care Unit: Toxoplasma gondii

“…20 During systemic inflammatory response syndrome and the compensatory anti-inflammatory response syndrome, the immune function may be impaired. [21][22][23][24] Individuals with immunity abnormalities such as ICU patients, who had been previously infected with T. gondii, may show increased IgG antibody titres or less frequently, increased titres of acute-phase antibodies, which may be interpreted as reactivation. T. gondii infection produces IgM, IgA, IgE and IgG antibodies, with the first three being detected early during the course of infection.…”