Sepsis. According to recent reports, sepsis affects between 20 and 30 million people worldwide every year, remaining a leading cause of death.76 The induction of hyporesponsiveness, or tolerance, acts a defense mechanism that decreases the response to inflammation maintaining homeostasis of the host. However, in many cases the immune sys- tem is unable to recover from this self-induced suppression, falling into an immunoparalysis state in which the host is unable to stop the progression of the infectious disease.24 In the last years, a grow- ing number of studies have shown how long-term reprogramming of cells after exposure to pathogens are of great importance for early cytokine production and for the induction of immunoparalysis and the establishment of disease tolerance.15 Monocytes from patients suffering from sepsis-induced immunoparalysis show reduced pro- inflammatory cytokine production with a defective capacity to mount glycolysis and 𝛽-oxidation.2 High levels of lactate and a low clearance rate can help predicting poor outcomes of septic states.77 However, the line between the development of tolerance or the induction of training is very thin. The development of immunoparal- ysis or the induction of trained immunity involves opposing regu- lation of common pathways20 and the blockade of a single step in oxidative phosphorylation switches the potential of LPS-stimulated macrophages from proinflammatory to anti-inflammatory.34 Tolerance and training are manifestations of the similar reprogramming pro- cesses, but with opposite consequences. Immune status in patients with sepsis or noninfectious systemic inflammatory response síndrome is altered.78 It has been known for long that IFN-𝛾 and GM-CSF can restore the responsiveness of monocytes from septic patients.79,80 Xxxxx et al. demonstrated that the immunostimulant effects of IFN- 𝛾 in these patients partially relied in the restoration of the metabolic defects of innate immunotolerance by promoting glycolysis.2 Admin- istration of 𝛽-glucan to mice induced proliferation of the progenitors of the myeloid lineage, which was associated with enhanced signal- ing by IL-1𝛽 and GM-CSF, and with adaptations in glucose metabolism and cholesterol biosynthesis, improving responses to secondary LPS challenge and protecing from myeloid-induced immunosuppression in mice.28 The intravenous injection of bone marrow stromal cells improved survival and organ function after cecal ligation and puncture in mice.81
Sepsis. A Health Crisis Sepsis is a syndromic, life-threatening condition that occurs when the body exerts an exaggerated response to infection and begins injuring its own internal organs [6]. Nearly 6% of the inpatient hospital population in the United States will carry a diagnosis of sepsis during their stay, incurring an aggregate hospital cost of $23.7 billion (USD) [5]. Even with the progress of diagnosis of sepsis, still 20% of septic patients progressed to deadly sever sepsis and sepsis shock.[8] When all hospital deaths are ultimately considered nearly 35% are attributable to sepsis, and interestingly, this extremely deadly condition lacks the notoriety of heart attacks which have a mortality rate of 2.7-9.6% and only cost the US $12.1 billion annually, roughly half of the cost of sepsis [5, 23]. In 2004 the Surviving Sepsis Campaign (SSC) promulgate the first of their many recommendations regarding treatment regimens for sepsis and septic shock in the form of consolidated evidence-based practice guidelines called sepsis bundles [8]. Numer- ous trials have demonstrated that outcomes for sepsis can be dramatically improved by early recognition of the condition and rapid treatment [1, 16, 3, 7]. The most recent recommendation from the SSC is a 1-hr bundle that in addition to obtaining diagnostic tests like cultures and lactate levels prescribes standard treatment with broad-spectrum antibiotics, IV fluid, and vasoactive drugs if necessary all within an hour of a sepsis diagnosis [12]. While there are effective protocols for treating sepsis once it has been diagnosed there still exists challenges in reliably identifying septic patients early in their course owing to the significant variability in the diseases presentation and xxxxxxxxxx.Xx present the Sepsis-3 guidelines have narrowed the constellation of signs and symptoms of sepsis into a definition that can be reliably used by clinicians and researchers to identify this life-threatening condition retrospectively, but this definition cannot be used to identify a patient who is experiencing the untoward effects of sepsis early in the disease’s course.
