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Clinical properties of sepsis
Sepsis is a potentially debilitating syndrome that results from the body's reaction to an infection in 90% of cases this is due to gram positive bacteria (Staphyloccoci and Streprococci ) and gram negative bacteria (Escherichia Coli, Pseudomonas Aeruginosa and Klebsiella species) the remaining 10% of causative agents can be attributed to a subset of bacteria known as Candida and viral/atypical organisms respectively 1. Regardless of the advances in medicine on how to manage sepsis, recent reports still document high mortality rates in patients with sepsis, with a mortality rate of 30% in the USA and 40% in the UK.2, 3-5. There are three kinds of septic conditions with increasing mortality as progress is made from one stage to another. The first stage can simply be described as sepsis with its defining feature been the systemic inflammatory response syndrome (SIRS), progressively the second stage is severe sepsis where a patient has sepsis but also the added complication of organ dysfunction. Finally the most serious and problematic type is septic shock whereby the patient is in a state of acute respiratory failure. When sepsis has the feature of organ failure, the mortality of the patient increases sharply and this feature marks the terminal stage of the condition which is generally geared towards death6.
The infection itself causes the body to begin a cascade of complex immunological responses which in theory are suppose to contain the infection and reduce any further damage to the body. However when the infection occurs the body goes into a whole body-wide inflammatory state known as SIRS (systemic inflammatory response syndrome) with the sole purpose of antagonising the effects of the invading pathogen to reduce its damage to tissues. Clinically the condition of SIRS has specific measurable defining features, which if two are fulfilled by a patient then a clinician can conclude they have SIRS7. These are:
Abnormal body temperature <36 ° and >38°
Abnormal heart rate i.e. tachychardia >90 mins-1
3. Respiratory rate >20 breaths min−1 or PaCO2 <4.3 kPa
4. Blood leucocyte count > 12 - 109/litre or < 4 - 109/litre or >10% immature (band) forms
Initially this inflammatory response, as well as other host defence mechanisms is mediated by the release and activation of agents of the innate and adaptive immune system. Some of these mediators include cytokines, neturophils, monocytes, macrophages and endothelial cells amongst others 8. Here I would focus on the actions of cytokines and some of their counterparts which secrete them. Cytokines are low molecular weight proteins or glycoprotein hormones 9-10, which can be produced by all tissues and most cells. They are usually produced and act locally but there a few that enter the systemic circulation and have significant physiological roles there9 Cytokines are concerned with restoring the natural function of the tissue in which they are produced especially when tissues are compromised during infection. However cytokines do have adverse effects when they are secreted in relatively copious amounts when tissues are critically challenged, this can lead to some of the symptoms that are seen in the SIRS state including fever, nausea, cachexia and a variety of homeostatic imbalances 9, 11-12 .The inflammatory response is a defensive mechanism which serves the purpose of reducing tissue damage by activating physiological adaptations and removing the pathogenic source. Some of these mechanisms have complex undertakings which involve a mirage of events that include dilatation of arterioles, venules and capillaries with increased vascular permeability, excretion of fluids including plasma proteins and migration of white blood cells into the inflammatory area2. The innate immune system plays a central role in the inflammatory process, as it cells (neutrophils and macrophages) are recruited during the pathogenic onslaught, these cells are found in most cells of the body and are the first on the scene when a pathogen is detected. Once activated, these cells go about releasing inflammatory mediators which are responsible for the clinical manifestations of inflammation2.
Pathogenesis of sepsis
The human body has some natural mechanical and chemical barriers which protect the delicate inner tissues from pathogenic micro-organisms. These physical barriers include the epithelial surfaces of the skin and the lining of the gut and respiratory tract. The chemical barriers are provided by secretions from these epithelial layers including hydrochloric acid in the stomach and antibacterial peptides in the gut and respiratory tract2. These barriers are good at preventing entry of foreign micro-organisms into the tissues. However When pathogenic micro-organisms such as bacteria, viruses and fungi infiltrate the external barriers of the body, they come into contact with cells of the innate (nonspecific) and adaptive immune system (specific) which go about minimising further tissue damage by localising and destroying any infiltrating and established pathogens 2 .
Cells in the body have what are known as toll-like receptors (TLRs) and cytoplasmic pattern recognition receptors (PRRs) on their surface. These receptors are designed to detect elements of foreign micro-organisms which are called 'pathogen associated molecular patterns' (PAMPs)13 . Different types of pathogens have their constituent molecules that are unique to them which make them identifiable by TLRs and PRRs. For example gram-negative bacteria can be detected by the presence of lipopolysaccharide (LPS), gram positive bacteria by their peptidoglycans and lipotheioic acid and viruses by their double stranded RNA molecules 2.
Having detected the presence of a pathogen the body then goes about initiating an 'intracellular signal transduction pathway' that leads to the stimulation of cytosolic nuclear factor (NF-kB). Once activated, NF-kB migrates from the cytoplasm to the nucleus and binds to transcription initiation sites in order to increase the transcription of certain cytokines such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10)14. The two latter cytokines are formidable pro-inflammatory cytokines which promote the process of inflammation.
Tumour necrosis factor- a (TNF-α), can be considered as one of the central mediators produced during the pro-inflammatory phase of sepsis. It's systemically released within one hour of pathogen entry and its levels in the plasma are one of the indicators of the severity of the septic syndrome. TNF-α is produced by monocytes, macrophages, lymphocytes, neutrophil granulocytes, mast cells, fibroblasts and endothelial cells when the host is challenged by bacterial toxins. Once released its effects are widespread throughout the body. Metabolically it induces the release of triglycerides from adipose tissue, promotes the release of amino acids from proteins and which cumulates in the breakdown of skeletal muscle. Some of the effects that are seen in SIRS are mediated by TNF-α, evidence of this is given by studies that use animal and human models to inject TNF-α. Once this happened SIRS resulted with other symptoms including fever, hemodynamic abnormalities, leukopaenia, and increased liver enzymes coagulopathy (defects in the coagulation system) and septic shock 2, 15-17.
Another cytokine produced during the pro-inflammatory acute phase of sepsis is interleukin 1-B (IL-1B). IL-Β is a subset of the IL-1 cytokine, along with its similar structured relative IL-1A. They both produce the same effects however IL-1B is the predominant cytokine seen in patients with sepsis. IL-1B is produced by monocytes, macrophages, polymorphonuclear (PMN) leucoytes and hepatocytes during the onset of an infection. IL-1B has several physiological effects including, the induction of fever by activating the hypothalamus, increases capillary permeability, hypotension and appetite suppression. Furthermore results from experiments using animal models and human participants have shown that administration of IL-1B causes fever, anorexia, malaise, arthralgia, and headache and haemodynamic abnormalities2.
These are the two main pro inflammatory cytokines that initiate their effects during the acute phase of sepsis. However alongside these there are also a few other key pro-inflammatory cytokines that are released. These are IL-6 and IL-8. IL-6 is also produced by a variety of cell types including lymphocytes, fibroblasts and monocytes. Like the others it has widespread effects including the activation of B and T lymphocytes, stimulation of the production of acute phase protein production in the liver and modulation of haemotopoiesis. It is also an indicator of the severity and outcome of sepsis as a concentration of IL-6 that is great than 1000 pg/mL is associated with a poor outcome2, 17-19.
Interleukin-8 is a cytokine which is produced by mononuclear phagocytes, polymorphonuclear leucocytes, lymphocytes, endothelial cells, epithelial cells and other mesothelial cell types especially in the presence of IL-Β, TNF-α and endotoxin. Its primary role is to activate and attract neutrophils to the site of tissue damage and inflammation. Once neutrophils have been exposed to IL-8, they go about adhering to endothelial cells, directing movement, enzyme secretion and increase the activity of the production of reaction oxygen metabolites 2. The concentration of IL-8 in septic patients peaks at 3-4 hours from pathogenic challenge. Studies which have administered IL-8 into human participants have shown not to cause septic shock however it was found that IL-8 does activate neutrophils to specific sites which lead could lead to tissue injury such as that seen in adult respiratory distress syndrome (ARDS) 20.
The pro-inflammatory phase of sepsis has also been found to be closely followed by is known as the anti-inflammatory phase, whereby anti-inflammatory cytokines are deployed in order to prevent further tissue damage from uncontrolled inflammation21. These anti-inflammatory cytokines include interleukin 10 (IL-10) and interleukin 8. Both of these cytokines have been shown to have an inhibitory effect on the production of TNF-α and IL-1. In animal studies it was found that IL-10 prevented endoxtin-morbidity and mortality during endotoxaemia 22-23. IL-4 also has been shown to inhibit the secretion of pro-inflammatory cytokines from monocytes/macrophages and neutrophils. 2 During this anti-inflammatory period an individual with sepsis is said to be highly immuno-compromised and susceptible to secondary infections. This state is known as a state of 'immunological anergy'. This state has been dubbed the compensatory anti-inflammatory response syndrome (CARS) by Bone 21.
Antagonising the effects of cytokines
Having briefly touched upon some of the deleterious effects of the cytokines it seems that the next logical step is to antagonise their action or production altogether in order to alleviate a patient from some of the harmful conditions associated with sepsis. A particular study called the MONARCS trial highlights this benefit 24. An anti TNF-α drug called afelimomab was trialled using 2634 patients found that afelimomab treatment was associated with improving survival and a reduction in IL-6 levels, there was also a greater reduction of the multi-organ dysfunction score compared with a placebo treatment suggesting that a blockade of TNF may be beneficial during sepsis. As in certain forms of sepsis like meningococcemia TNF-α levels are high and are associated with mortality, reducing their levels will be logical 25-27. However studies have shown that the exaggerated levels of TNF in an elevated systemic inflammatory response may be lower than assumed 25, 28-31. Debets et al found that 11 out of 43 patients had detectable circulating TNF (detection limit of 5 to 10 pg/ml) 28. This suggests that in cases where TNF-α is below a certain threshold it may not be effective to simply use antagonistic drugs against them if their levels are low to begin with. Further doubt about the efficacy of anti-TNF drugs is strengthened by a study which demonstrated that that blocking TNF-α worsened survival 32-33. Also, the idea of death from sepsis been attributed to an over stimulated immune system came from studies that were based on animals that did not represent the real clinical picture of sepsis in humans 34-35.This is because they used large doses of endotoxin and bacteria which meant that levels of TNF-α were subsequently higher in these animals than in patients 35.
Recombinant IL-1 antagonist has been shown to reduce mortality in rabbits that would have otherwise died from septic shock. These rabbits were administered with 100 mg kg-1 of IL-1ra and made a full recovery after 7 days 36. Gross examination of their lungs showed that there was bleeding but no significant pathological changes to the structure of their lung tissue. Furthermore microscopic examination revealed that there was no evidence of the cellular changes that took place in the group of rabbits that had been administered with the endotoxin alone36. However these studies used animal models which may not be truly representative of the conditions that are present in humans.
Various other studies using clinical trials of patients with differing levels of septic severity have found insignificant differences in the mortality rate of patients given IL-RA and patients given a placebo 37. Nevertheless a small beneficial effect was found; however, overall these studies show that targeting a single inflammatory mediator alone is unlikely to improve the outcome of sepsis.
The fact that anti-TNF and anti-IL-1 strategies have failed to prevent death in septic patients could be an indication of the difficulty in designing clinical trials 37. Another problem is that patients often come to medical attention relatively late in the condition, therefore the cytokines which these drugs are trying to target have already dealt their effects. This means that possibly blocking these cytokines may be too late37.
High mobility group 1 cytokine
All hope has not been lost as another cytokine-like product has been identified called high mobility group box 1 (HMGB1); it was found that it was a late mediator of lethal systemic inflammation in animal models which resulted in delayed endotoxin lethality and systemic inflammation 38-39. Studies have shown that HMGB1 contributes to a number of pathophysiological processes, including antibacterial activity40 cell differentiation41, myocardial regeneration42 amongst other things, but most relevantly it has been described as a potent pro-inflammatory cytokine which associates with a number of inflammatory diseases especially sepsis39, 43-46. Therefore targeting the pro-inflammatory cytokine HMGB1 may be a potent therapeutic target that can have more significant effects on decreasing, or even eliminating the mortality of sepsis in patients. Recent evidence pointing in this direction has highlighted the benefit of HMGB1 antagonists such as ethyl pyruvate (EP) 47, Oleanoic acid (OA) 38, Edaravone48, Gabexate Mesilate (GM) 38. These antagonists have increased survival in studies using mouse models and have been beneficial in neonatal sepsis. These results suggest that HMGB1 antagonists may be a future therapeutic target for patients with sepsis.
Sepsis is a complicated syndrome with high morbidity and mortality rates, which has complex pathophysiology that this essay has only scratched the surface of. Antagonising the action of cytokines in theory should translate into a significant decrease in the mortality of patients with sepsis, however in practice this is not the case. This could be attributed to poor study design and to the fact that the antagonist is administered too late to be effective. Nevertheless various antagonists have shown to be beneficial in certain types of sepsis which suggests that their applications can be beneficial in these cases. Conversely IL-10 and TNF-α are important immune defences that help contain the infection and recruit further immune cells to the site of infection in order to minimise further tissue damage. Therefore completely inhibiting them or inhibiting them too early may severely compromise the patient's immune capabilities leading to secondary infections which can be fatal.
In light of this, I am of the opinion that treatment for sepsis taking the antagonising route should be tailored to each patient's unique clinical features. It may also possibly be beneficial if it is administered early upon admission to hospital to have maximum efficacy. Furthermore administering these antagonists with the combination of other therapies may be a powerful treatment plan that may alleviate the mortality of sepsis.
Since studies have given mixed results it is clear that rather than studying the benefits of cytokine antagonists by themselves, it may be beneficial to see if they will be more effective if used in combination with other therapies. Current studies have not shown any significant benefit of antagonising cytokines in order to improve patient outcome with sepsis, however studies using a relatively new cytokine antagonists for HMGB1 have shown that it may be possible. Future studies can also implement this cytokine using human participants to see if in fact it will be effective in a clinical setting.