Editing Sepsis (section)

== History ==
[[File:'ware Hitler's Greatest Ally Art.IWMPST14196.jpg|thumb|upright|Personification of ''septicemia'', carrying a spray can marked "[[Poison]]"]]

The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of [[decomposition|decay or decomposition]] of organic matter.<ref name=Geroulanos2006/><ref name="CavaillonAdrie2008"/><ref name="pmid18171697"/> In the eleventh century, [[Avicenna]] used the term "blood rot" for diseases linked to severe [[Pus|purulent]] process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term&nbsp;– sepsis&nbsp;– was used for this condition.

The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. The [[International Statistical Classification of Diseases and Related Health Problems]] (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia".<ref name="aapc"/> All those diagnoses have been converted to sepsis, again with modifiers, in [[ICD-10]], such as "Sepsis due to streptococcus".<ref name="aapc">{{Cite web |url=https://www.aapc.com/blog/11406-understand-how-icd-10-expands-sepsis-coding/ |title=Understand How ICD-10 Expands Sepsis Coding – AAPC Knowledge Center | vauthors = Stewart C |website=AAPC |date=8 April 2011 |language=en-US |access-date=2020-02-06}}</ref>

The current terms are dependent on the microorganism that is present: [[bacteremia]] if [[bacteria]] are present in the blood at abnormal levels and are the causative issue, [[viremia]] for [[viruses]], and [[fungemia]] for a [[fungus]].<ref name=Merck/>

By the end of the 19th century, it was widely believed that [[microbes]] produced substances that could injure the [[mammalian]] host and that soluble [[toxins]] released during infection caused the fever and shock that were commonplace during severe infections. [[Richard Friedrich Johannes Pfeiffer|Pfeiffer]] coined the term [[endotoxin]] at the beginning of the 20th century to denote the pyrogenic principle associated with ''[[Vibrio cholerae]]''. It was soon realized that endotoxins were expressed by most and perhaps all [[gram-negative bacteria]]. The [[lipopolysaccharide]] character of enteric endotoxins was elucidated in 1944 by Shear.<ref name=Shear1944/> The molecular character of this material was determined by Luderitz et al. in 1973.<ref name=Luderitz1973/>

It was discovered in 1965 that a strain of C3H/HeJ [[mouse]] was immune to the endotoxin-induced shock.<ref name=Heppner1965/> The genetic locus for this effect was dubbed ''Lps''. These mice were also found to be hyper-susceptible to infection by gram-negative bacteria.<ref name=Obrien1980/> These observations were finally linked in 1998 by the discovery of the [[toll-like receptor]] gene 4 (TLR 4).<ref name=Poltorak1998/> Genetic mapping work, performed over five years, showed that TLR4 was the sole candidate locus within the Lps critical region; this strongly implied that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin-resistant phenotype was discovered to be due to a mutation in the [[cytoplasm]].<ref name=Poltorak1998B/>

Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies,<ref>{{cite journal | vauthors = Korneev KV | title = [Mouse Models of Sepsis and Septic Shock] | journal = Molekuliarnaia Biologiia | volume = 53 | issue = 5 | pages = 799–814 | date = 18 October 2019 | pmid = 31661479 | doi = 10.1134/S0026893319050108 | s2cid = 204758015 | doi-access = free }}</ref> and more careful design of preclinical studies.<ref name=Lewis2016/><ref name=Mills2016/><ref name=Engber2013/><ref name="pmid23401516"/> One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identify [[biomarkers]] and [[drug target]]s for intervention.<ref name=Haseldine2016/>