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

Roger C. Bone, MD
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From Rush-Presbyterian-St. Luke's Medical Center and Rush Medical College, Chicago, Illinois. For the current author address, see end of text. Requests for Reprints: Roger C. Bone, MD, Rush-Presbyterian-St. Luke's Medical Center, Rush Medical College, Offices of the Dean, 600 South Paulina, Suite 202, Chicago, IL 60612.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;125(8):680-687. doi:10.7326/0003-4819-125-8-199610150-00009
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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.


Grahic Jump Location
Figure 1. Stage 1 begins at a site of local injury or infection. Proinflammatory mediators are released locally to promote wound healing and to combat foreign organisms or antigens. Anti-inflammatory mediators are then released to downregulate this process. If the original insult is small and the patient is healthy, homeostasis will be quickly restored. Stage 2 occurs if local defense mechanisms are insufficient to correct the local injury or eliminate the local infection. Through various mechanisms, proinflammatory mediators are released into the systemic circulation; these recruit additional cells to the local area of injury. Systemic release of anti-inflammatory mediators follows soon thereafter; under normal circumstances, these mediators ameliorate the proinflammatory reaction and restore homeostasis. Stage 3 occurs if the systemic release of proinflammatory mediators is massive or if the anti-inflammatory reaction is insufficient to permit downregulation. It is at this stage that most patients have symptoms of the systemic inflammatory response syndrome (SIRS), as well as incipient evidence of the multiple organ dysfunction syndrome (MODS). Stage 3 can be represented by excessive systemic levels of anti-inflammatory mediators that develop as a response to a massive proinflammatory response; however, these levels can also develop de novo. Patients with a stage 3 compensatory anti-inflammatory response syndrome (CARS) response have marked immunosuppression and thus are at increased risk for infection. If the body can reestablish homeostasis after stage 3 or 4, the patient may survive. Stage 5 is the final stage of MODS. At this stage of immunologic dissonance, the balance between pro- and anti-inflammatory mediators has been lost. Some patients may have persistent, massive inflammation; others may have ongoing immunosuppression and secondary infections. Still others may oscillate between periods of inflammation and immunosuppression.
The five stages in the development of multiple organ dysfunction.
Grahic Jump Location




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