Sepsis [σήψις] is the original Greek word for the “decomposition of animal or vegetable organic matter in the presence of bacteria.” The word is found for the first time in Homer’s poems, where Sepsis is a derivative of the verb form sepo [σήπω], which means “I rot.” The term sepsis is also found in the Corpus Hippocraticum exchangeably with the word sepidon [σηπεδών] (“the decay of webs”): Epidemic. B. 2,2, Prorret. I. 99. Aristoteles, Plutarch, and Galen use the word sepsis [σηψις] in the same meaning as Hippocrates.1
This original meaning connoted decay and wound putrefaction and described a process of decomposition of organic matter and tissue breakdown resulting in disease (foul odor, pus formation, dead tissue) and eventually to death.2 Thus, the word sepsis has persisted for 2700 years with more or less unchanged meaning. Subsequent works just confirmed the causal link between microbes and suppurative infections or systemic symptoms and clinical findings from infections establishing the infections as the underlying disease. Hugo Schottmuller in 1914 founded the modern definition of sepsis and was the first to describe that the presence of an infection was a fundamental component of the disease.3
In 1972, Lewis Thomas described sepsis in the following way: “It is our response to [the microorganism’s] presence that makes the disease. Our arsenals for fighting off bacteria are so powerful … that we are more in danger from them than the invaders.” and popularizing the theory that “…it is the [host] response … that makes the disease.”4 Finally, the concept entered into daily clinical practice when Roger Bone and colleagues defined sepsis as a systemic inflammatory response syndrome that can occur during infection.5
In recent years this syndromic characterization of sepsis has been expanded to SIRS (systemic inflammatory response syndrome), CARS (compensatory anti-inflammatory response syndrome), and MARS (mixed antagonists response syndrome), with recognition that immune dysfunction during sepsis may be a significant aspect of pathogenesis.6,7
Currently sepsis is considered a host immune response to infection, which clinically results in a continuum of disease categorized as sepsis, severe sepsis, septic shock, and multiorgan failure (MOF). Also, sepsis is the maladaptive immune response of the host to invading pathogens in normally sterile sites of the body. In severe sepsis and septic shock this inappropriate immune response to infection leads to mismatch of host response to the pathogenic stimuli so profound as to finally lead to cellular dysfunction and ultimately to organ injury and dysfunction or failure.
The immune profile of this host-pathogen mismatch can be predominately proinflammatory (systemic inflammatory response syndrome, SIRS), mixed (mixed antagonistic response syndrome, MARS), or anti-inflammatory (compensatory anti-inflammatory response syndrome, CARS). The final result is various degrees of hyperinflammation, immunosuppression, abnormal coagulation, and microcirculatory dysfunction, all which may contribute to organ injury and cell death.2,6
Clinical diagnosis of severe sepsis or septic shock although valuable and of significant importance for the management of septic patients may lead to extremely heterogeneous cohorts in terms of patients’ immunological status. This heterogeneity offers one explanation for the failure of prior trials of biologic therapies for sepsis, since treatments that focused on attenuating the initial inflammatory response of sepsis in a sense ignored and in fact might have exacerbated the progressive development of immunosuppression in some patients.8-11
Immune status characterization during the course of sepsis may identify patients who could benefit from immunotherapy tailored to their particular circumstances. These patients may be those who develop septic shock and die early from multiorgan failure or those who develop late immunosuppression after surviving the initial septic shock but fail to completely recover from persisting sepsis syndrome. The latter patients often develop what appears to be chronic sepsis, with recurrent nosocomial infections and eventual recurrent and refractory septic shock. In a sense these patients may be considered to have yet another organ system failing in the face of sepsis—their immune system.
NATURAL HISTORY OF INFECTION AND SEPSIS SYNDROME
Sepsis is a major health care problem due to the high morbidity and mortality of the syndrome, which has very high health care costs. Despite intense research and recent advances in treatment, mortality remains extremely high, reaching 40% to 60% in high-risk patient populations.
Infections caused by diverse microorganisms and involving many different body sites may present as SIRS, which is a clinical syndrome defined by (a) hyperthermia >38.0°C or hypothermia <36.0°C, (b) tachycardia (heart rate >90/min), (c) tachypnea (respiratory rate >20 per minute) or hyperventilation ( <32 mm Hg), (d) leucocytosis (WBC count >12.000/mm3) or leukopenia (WBC count <4.000/mm3 or the presence of >10% immature neutrophils (bands) as defined by the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference.12 SIRS driven by infection progresses along a continuum, described as sepsis, severe sepsis, septic shock, and multisystem organ failure. Along this continuum the host’s immune system is operating at varying levels of activation, driven by complex interactions between the host and infectious agent(s). Host immune response includes innate immune response that incorporates humoral and cellular components. The humoral component includes release of cytokines, chemical substances that are directly toxic to invading microbes or that act as mediators for immune cell activation. The cellular component includes circulating monocytes, tissue macrophages, neutrophils, and lymphocytes.
As a result of the actions of the innate immune system tissue macrophages engulf and digest pathogens, produce cytokines, and present pathogen particles (antigens) to lymphocytes, providing linkage to the adaptive immune system. Neutrophils are attracted by chemokines and migrate to infected tissues where they phagocytose pathogens and secrete toxic substances such as reactive oxygen species (ROS) that destroy invading microorganisms. Eosinophil and basophil granulocytes secrete mediators creating an inflammatory milieu locally in the infected tissues and systemically in the circulation. As a consequence peripheral leukocytosis is observed due to bone marrow stimulation with left shift of neutrophils (immature forms), dilation and leakage of the adjacent vessels due to the action of vasoactive inflammatory mediators (NO) to facilitate the migration of inflammatory cells into the infected tissue, which leads to efflux of plasma into tissues. Taken all together these processes lead to clinical signs of local inflammation, including redness (rubor), swelling (tumor), increased temperature (calor), and pain (dolor).
Thus, infection may present with signs and symptoms of SIRS and may resolve with the use of antibiotic and/or other supportive measures. Normally, the immune system controls local inflammation and eradicates invading pathogens. When local control mechanisms fail, however, systemic inflammation and then sepsis occurs.
Cells of the innate immune system recognize molecular patterns of most microbes including viruses, bacteria, fungi, and protozoa to produce inflammation at the local level or systemically. Thus inflammation starts when damage-associated molecular patterns (DAMPs) bind to immune cell pattern recognition receptors (PRRs), which rapidly initiate host defense responses. DAMPs are both pathogen-associated molecular patterns (PAMPs) that are expressed by both invading and innocuous microorganisms and intracellular proteins or mediators that are released from damaged tissues and dying cells, which are known as alarmins such as high mobility group box 1 and S100a proteins. PAMPs include lipopolysaccharides (LPS, endotoxin) contained in the cell wall of gram-negative bacteria, lipoteichoic acid and peptidoglycan from gram-positive bacteria, bacterial DNA, or viral RNA. PRRs include Toll-like receptors (TLRs), intracellular NOD proteins, and peptidoglycan recognition proteins.
The recognition, binding, and interaction of DAMPs (eg, LPS) by PRRs (eg, TLRs) located on the immune cell surface result in signal transduction and in turn to a complex intracellular cascade of enzymes (kinases), which activate proteins. These proteins activate additional intracellular pathways leading to activation of transcription factors within the cell nucleus binding to DNA, thus activating hundreds of specific genes coding for proteins, which are increased during the inflammatory process in a time-dependent fashion. For example, in gram-negative sepsis LPS binds to TLR4 and CD 14 activating myeloid differentiation protein (MyD)-88, which then activates interleukin-1 receptor–associated kinase (IRAK), which, in turn, stimulates the tumor necrosis factor receptor–associated factor (TRAF) and, consequently, the TRAF-associated kinase (TAK). As a result, the nuclear transcription factor, nuclear factor kappa B (NFκB), is liberated from its inhibitor (IκB) and is able to dislocate into the cell nucleus and bind to DNA and modulate gene function.13-15
During sepsis high levels of circulating DAMPs from invading microorganisms and/or damaged host tissue activate host immune cells, leading to inflammation characterized by the so-called cytokine storm. The early phase of sepsis creates a proinflammatory environment, which is caused by the excessive activation of the host immune system by tissue damage and/or severe infection, leading to severe dysregulation of various body systems.16 Central hubs of the inflammatory response during sepsis include the complement anaphylatoxin C5a, macrophage migration-inhibitory factor (MIF), Toll-like receptor 4 (TLR4), high-mobility group box 1 protein (HMGB1), interleukin-17A (IL-17A) but also the coagulation, the endocrine, the innate and adaptive immune, and the autonomic nervous systems (adrenergic and cholinergic pathways).3
One of the significant molecules produced during sepsis is TNF, which propagates inflammatory pathways in multiple organ systems and also plays a very important role in the activation of programmed cell death or apoptosis. Also, interleukin (IL)-6 induces the production of acute phase proteins in the liver, for example, C-reactive protein and fibrinogen. Another enzyme activated during sepsis is inducible nitric oxide synthase (iNOS) leading to nitric oxide (NO) production and finally cyclic guanosine monophosphate (cGMP) that leads to local and systemic vasodilation, which correlates clinically to hypotension and shock.17
Vasodilation and intravascular volume depletion from increased capillary leak and external losses observed in early sepsis lead to underfilling of the heart and a low cardiac output, which in conjunction with myocardial depression potentially causes an oxygen supply-demand imbalance in various organ beds. Further imbalance may occur due to decreased oxygen delivery to the tissues by alterations of the microcirculation observed in patients with sepsis.18 Following adequate volume resuscitation patients typically exhibits high cardiac output hypotension, although during the early hours to days of sepsis a propensity for continued loss of intravascular volume persists often resulting in recurrent hypovolemia and requiring the clinician managing the patient with septic shock to repeatedly return to the question of whether additional intravascular volume is needed.
Also, the inflammatory insult of sepsis appears capable of causing structural and functional damage to the mitochondria.19,20 Mitochondrial dysfunction may be due to direct inhibition of the respiratory enzyme complexes from increased concentrations of nitric oxide and its metabolite, peroxynitrite, and by direct damage from increased production of reactive oxygen species. Also, recent studies report a genetic downregulation of new mitochondrial protein formation, which is associated with intramitochondrial defense mechanisms (glutathione, superoxide dismutase) being depleted or overwhelmed.21,22
The therapeutic window during this initial hyperinflammatory response for initiating treatment with anti-inflammatory drugs is likely narrow (<24 hours), after which a treatment to increase immune function may be more beneficial. This may in part explain a number of negative therapeutic trials directed at reducing inflammatory mediators in septic patients. Evidence from several studies has shown that certain anti-inflammatory pathways seem activated very early in septic patients.23-25 The systemic anti-inflammatory response may be useful for the attenuation of deleterious systemic proinflammatory effects and the concentration and compartmentalization of the inflammation at the site of infection.26
However, when anti-inflammatory mechanisms dominate, the immune system is depressed, a condition termed immunoparesis or immunoparalysis, and the body’s susceptibility to nosocomial infections and the reactivation of dormant pathogens such as cytomegalovirus is increased.27,28 The state of immunoparesis is associated with declining levels of numerous hormones, a reduced metabolic rate, and in some tissues frank bioenergetic failure. The observation of these responses to infection has raised the hypothesis that immune system stimulation during this phase of sepsis could be beneficial.29,30 Similar to the notion of SIRS, this phase of the course of sepsis has been termed the compensatory anti-inflammatory response syndrome (CARS). Interestingly, it seems most deaths related to sepsis occur during this phase.