mortality of 40% and those with a level of less than 2 mmol/l having a mortality of less than 15%. there are a number of prognostic stratification systems, such as apache ii and mortality in emergency department sepsis. apache ii factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. of the individual covariates, the severity of the underlying disease most strongly influences the risk of death. septic shock is also a strong predictor of short- and long-term mortality. case-fatality rates are similar for culture-positive and culture-negative severe sepsis. the mortality in emergency department sepsis (meds) score is simpler and useful in the emergency department environment. some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or to study. epidemiology sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. the number of new cases worldwide of sepsis is estimated to be 18 million cases per year. in the united states sepsis affects approximately 3 in 1,000 people, and severe sepsis contributes to more than 200,000 deaths per year. sepsis occurs in 1–2% of all hospitalizations and accounts for as much as 25% of icu bed utilization. due to it rarely being reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are likely underestimated. a study of u.s. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010. it is the second-leading cause of death in non-coronary intensive care unit (icu) and the tenth-most-common cause of death overall (the first being heart disease). children under 12 months of age and elderly people have the highest incidence of severe sepsis. among people from the u.s. who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long-term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care. a study of 18 u.s. states found that, amongst people with medicare in 2011, sepsis was the second most common principal reason for readmission within 30 days. several medical conditions increase a person's susceptibility to infection and developing sepsis. common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as cancer, diabetes, or the absence of a spleen; and major trauma and burns. from 1979 to 2000, data from the united states national hospital discharge survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. however, the global prevalence of sepsis has been estimated to be higher in women. during the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. however, according to the nationwide inpatient sample from the united states, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for population aged more than 18 years. the incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by sixth decade of life. the increase in the average age of the population, alongside the presence of more people with chronic diseases or on immunosuppressive medications, and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis. history 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 decay or decomposition of organic matter. in the eleventh century, avicenna used the term "blood rot" for diseases linked to severe purulent process. though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term – sepsis – 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". all those diagnoses have been converted to sepsis, again with modifiers, in icd-10, such as "sepsis due to streptococcus". 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. 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. 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. the molecular character of this material was determined by luderitz et al. in 1973. it was discovered in 1965 that a strain of c3h/hej mouse was immune to the endotoxin-induced shock. the genetic locus for this effect was dubbed lps. these mice were also found to be hyper susceptible to infection by gram-negative bacteria. these observations were finally linked in 1998 by the discovery of the toll-like receptor gene 4 (tlr 4). genetic mapping work, performed over a period of 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. 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, and more careful design of preclinical studies. 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 targets for intervention. society and culture economics sepsis was the most expensive condition treated in united states' hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase. by payer, it was the most costly condition billed to medicare and the uninsured, the second-most costly billed to medicaid, and the fourth-most costly billed to private insurance. education a large international collaboration entitled the "surviving sepsis campaign" was established in 2002 to educate people about sepsis and to improve outcomes with sepsis. the campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years. the guidelines were updated in 2016 and again in 2021. sepsis alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals. research phenotypic strategy switches of microbes capable of provoking sepsis some authors suggest that initiating sepsis by the normally mutualistic (or neutral) members of the microbiome may not always be an accidental side effect of the deteriorating host immune system. rather it is often an adaptive microbial response to a sudden decline of host survival chances. under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass as decomposers, and then transmitted through soil or water to establish mutualistic relations with new individuals. the bacteria streptococcus pneumoniae, escherichia coli, proteus spp., pseudomonas aeruginosa, staphylococcus aureus, klebsiella spp., clostridium spp., lactobacillus spp., bacteroides spp. and the fungi candida spp. are all capable of such a high level of phenotypic plasticity. evidently, not all cases of sepsis arise through such adaptive microbial strategy switches. paul e. marik's "marik protocol", also known as the "hat" protocol, proposed a combination of hydrocortisone, vitamin c, and thiamine as a treatment for preventing sepsis for people in intensive care. marik's own initial research, published in 2017, showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media and national public radio, leading to criticism of science by press conference from the wider medical community. subsequent independent research failed to replicate marik's positive results, indicating the possibility that they had been compromised by bias. a systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed. another more recent review found that "hat therapy significantly reduced the duration of vasopressor use and improved the sofa score but appeared not to have significant benefits in other outcomes for patients with sepsis." overall, the evidence for any role for vitamin c in the treatment of sepsis remains unclear as of 2021.