User:Peter Georgiev/sandbox
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Sepsis is a life-threatening disorder which typically develops following infection or an inflammatory insult.[1]
Definition
The pathogenesis of the disease is associated with a harmful and damaging host response to such infection. The clinical hallmarks of sepsis include inappropriate or prolonged inflammation, immunosuppression, the inability to clear infection and a strong predisposition to nosocomial infections.[1] Currently, researchers view sepsis as a problem attributed to an immune system that is both highly compromised and unable to eradicate pathogen.[3] Generically, sepsis is defined as the systemic inflammatory response that occurs during infection or SIRS; systemic inflammatory response syndrome. The syndrome develops as inflammation becomes progressively exaggerated, dysregulated and ultimately uncontainable. Exaggerated inflammatory responses are normally down-regulated by compensatory inflammatory responses [CARS] responsible for terminating inflammation. Failure to contain infections and the ability to properly orchestrate inflammatory responses by disruption of either SIRS or CARS can lead to severe sepsis, septic shock and multiple organ failure. Disruption of inflammatory homeostasis during sepsis propagates cellular and immune cell dysfunction, results in multiple organ failure and eventually leads to an irrecoverable state. Dysregulation of the inflammatory response leads to both the disruption and damage of the host’s immune system and contributes to an immuno-comprised state characterized by cellular anergy and apoptosis.[2]
SIRS & CARS
Septic inflammatory responses involve two distinct but mutually inclusive phases: the systemic inflammatory response [SIRS] and the compensatory anti-inflammatory response [CARS].[1] SIRS acts as an effective inflammatory response towards pathogen or injury and is countered by CARS which acts to terminate inflammation in-vivo post incidence with the infectious agent.[1] SIRS & CARS can be viewed as a balanced response of pro-inflammatory mediators [SIRS] resulting from inflammatory insult or infection, and anti-inflammatory mediators [CARS] responsible for properly terminating SIRS once infection is contained. In sepsis, SIRS begins as a pro-inflammatory mediated response to the inciting agent and leads to a progressive inflammatory response usually accompanied by uncontained infection and secondary injuries. Secondary injuries in turn lead to immunosuppression and reduced containment of infection accompanied by damage to epithelial and endothelial cell barriers. Once such barriers are overcome, infection is usually further disseminated and results in multiple organ failure, cellular apoptosis and ultimately host death.[1] The intensity of SIRS & CARS, as well as the ability to attain mutual balance between each phase influences host survival in sepsis. Inappropriate responses of either SIRS or CARS can contribute to the dysregulation of a functional inflammatory response. Exaggeration of either response can likely result in host damage due to the loss of a regulated expression of SIRS & CARS mediators. As a result hyper or hypo-inflammation driven irregularities can directly contribute to cell-mediated immune dysfunction.
SIRS & CARS Treatment
In order to properly target inflammatory responses in vivo, potential therapeutic pro & anti-inflammatory mediators must be tailored and to the known intensity and bias of the patients’ inflammatory status.[1] Diverse therapies against various inflammatory agents, including bacterial toxins, host-derived mediators and coagulation cascades have shown a dramatic promise in the attenuation of inflammatory dysregulation in several animal models but the transition to clinical trials has been at best modest.
History of Definition
One of the hallmarks of sepsis has been the apparent lack of a clinical definition necessary to characterize heterogeneous patient populations. For half a century, sepsis has been defined as the systemic host response that occurs during infection. Despite numerous sub classifications made to this generic definition, sepsis remained to be viewed as a syndrome arising from the host’s own response to pathogen. In order to fulfill the initial need for a clinical definition a consensus conference defined sepsis as the systemic inflammatory response syndrome that occurs during infection.[4] This definition of sepsis gave the syndrome a set of clinical symptoms associated with bacteremia or the presence of bacteria in the bloodstream.[4] Initially physicians believed the presence of bacteremia was a secure clinical sigh of sepsis as many patients exhibiting clinical signs of sepsis also exhibited definable levels of bacteremia. In virtue of this the terms sepsis and septicemia were widely interchanged in clinical settings. Despite that, sepsis encompasses a wide range of processes, which range from a severe and lethal form of sepsis known as meningococcemia to the often mild, limited, and beneficial response to the rhinoviral infection. Consequently a need for well defined entry criteria for patients who did not have measurable levels of bacteremia but exhibited signs of sepsis created the need for a definition able to encompass a wide range of processes such as meningococcemia. Because patients did not always exhibit definable levels of bacteria a consensus conference orchestrated by the Society of Critical Care Medicine introduced the term SIRS which did not require an intrinsic bacterial infection from the host.[4] In order to further account for and classify disease stages not associated with bacterial presence in the blood the terms septic shock and severe sepsis were also introduced to account for intrinsic clinical stages of SIRS.[4] Because patients did not always exhibit definable levels of bacteria a consensus conference orchestrated by the Society of Critical Care Medicine introduced the term SIRS which did not require an intrinsic bacterial infection from the host.[4] In order to further account for and classify disease stages not associated with bacterial presence in the blood the terms septic shock and severe sepsis were also introduced to account for intrinsic clinical stages of SIRS.[4]
References
Buras JA, Holzmann B, Sitkovsky M: Animal models of sepsis: setting the stage. Nat Rev Drug Discov 2005, 4:854-865[1]
Ward et all. The enigma of Sepsis. J Clin Invest 2003: 112(4): 460-467[2]
Hotchkiss, R. S., C. M. Coopersmith, J. E. McDunn, and T. A. Ferguson. 2009. The sepsis seesaw: tilting toward immunosuppression. Nat Med 15:496[3]
Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med 29, 1303–1310 (2001).[4]