Sepsis - Causes and Pathogenesis

Causes of sepsis

The main pathogens in patients with sepsis are considered to be highly virulent gram-negative and anaerobic bacteria, and less often gram-positive flora.

The most frequently isolated bacteria in sepsis are E. coli, S. aureus, S. pneumoniae and obligate anaerobes.

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Pathogenesis of sepsis

After the introduction of terms and concepts proposed at the Consensus Conference by R. Bon and co-authors in 1991 into clinical practice, a new stage in the study of sepsis, its pathogenesis, principles of diagnosis and treatment began. A single set of terms and concepts focused on clinical signs was defined. Based on them, quite definite ideas about the pathogenesis of generalized inflammatory reactions have now been formed. The leading concepts have become "inflammation", "infection", "sepsis".

The development of systemic inflammatory response syndrome is associated with a disruption (breakthrough) of the local inflammation boundary function and the entry of proinflammatory cytokines and inflammation mediators into the systemic bloodstream. The clinical picture corresponding to these mechanisms is quite typical (temperature reaction, leukocytosis (leukopenia or left shift in the leukocyte formula), tachycardia and tachypnea). Such symptoms are similar to the symptoms inherent in the hyperergic type of sepsis in most patients. Treatment regimens developed based on the experimental results give very good results, as a rule, in the preclinical phase of testing. At the same time, one can find a huge number of publications on failures that befell seemingly excellent drugs in their idea (for example, anti-cytokine monoclonal antibodies) during clinical phases of testing. All this leads to the conclusion that the hyperergic reaction is not the only way to implement systemic inflammation.

By now, quite numerous groups of mediators are known that perform the function of stimulating the inflammatory process and anti-inflammatory protection. Table 23-2 presents some of them.

The hypothesis of R. Bon et al. (1997) on the patterns of development of the septic process, currently accepted as the leading one, is based on the results of studies confirming that the activation of chemoattractants and proinflammatory cytokines as inducers of inflammation stimulates the release of counteragents - anti-inflammatory cytokines, the main function of which is to reduce the severity of the inflammatory response.

This process, which follows immediately after the activation of inflammation inducers, is called "anti-inflammatory compensatory reaction", in the original transcription - "compensatory anti-inflammatory response syndrome (CARS)". In terms of severity, the anti-inflammatory compensatory reaction can not only reach the level of the pro-inflammatory reaction, but also exceed it. Unfortunately, it is almost impossible to detect obvious clinical signs of a particular degree of activity of these systems. This is especially difficult to do at the early stages of the process due to the ongoing neurohumoral consequences of the "pro-inflammatory mediator explosion" with typical signs of a systemic inflammatory reaction of the body. This condition is proposed to be called the syndrome of mixed antagonist reaction, in the original transcription - "mixed antagonists response syndrome (MARS)".

The absence of obvious clinical signs is the argument of skeptics when they raise the question of the advisability of isolating such a reaction at all. However, the conducted studies of the dynamics of the activity of some proinflammatory and anti-inflammatory cytokines on the surface of monocytes circulating in the peripheral blood made it possible to determine a sharp increase in the activity of IL-4 with reduced activity of interferon-y and IL-2. It was shown that important criteria of the anti-inflammatory compensatory reaction, accessible for laboratory determination, can be: a decrease in the level of HLA-DR expression on the surface of monocytes to 30% and below, as well as a decrease in the ability of macrophages to synthesize proinflammatory cytokines TNF-a and IL-6.

Based on this, the following are currently proposed as diagnostic criteria:

• for the anti-inflammatory compensatory reaction syndrome - a decrease in the level of HLA-DR expression on the surface of monocytes to 30% and below, as well as a decrease in the ability to synthesize pro-inflammatory cytokines TNF-a and IL-6;
• for mixed antagonistic reaction syndrome - clinical signs of a systemic inflammatory reaction in patients with immunological criteria for anti-inflammatory compensatory reaction syndrome.

It is known that when determining freely circulating cytokines, the probability of error is so significant (without taking into account cytokines on the cell surface) that this criterion cannot be used as a diagnostic criterion for the syndrome of anti-inflammatory compensatory reaction.

When assessing the clinical course of the septic process, four groups of patients can be distinguished:

1. Patients with severe injuries, burns, purulent diseases, who do not have clinical signs of systemic inflammatory response syndrome and the severity of the underlying pathology determines the course of the disease and prognosis.
2. Patients with sepsis or severe diseases (trauma), who develop moderate systemic inflammatory response syndrome, experience dysfunction of one or two organs, which recovers fairly quickly with adequate therapy.
3. Patients who rapidly develop a severe form of systemic inflammatory response syndrome, which is severe sepsis or septic shock. Mortality in this group of patients is highest.
4. Patients whose inflammatory response to primary damage is not so pronounced, but organ failure progresses within a few days after the signs of the infectious process appear (such dynamics of the inflammatory process, which has the form of two peaks (two-hit), is called the "two-humped curve"). Mortality in this group of patients is also quite high.

Every physician who has experience working with patients with severe forms of surgical infection can consider this idea of the types of sepsis to be justified. Any of these variants of the infectious process is quite common in clinical practice. However, is it possible to explain such significant differences in the clinical course of sepsis by the activity of proinflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process proposed by R. Bon et al. According to it, five phases of sepsis are distinguished:

1. Local reaction to damage or infection. Primary mechanical damage leads to activation of proinflammatory mediators, which differ in their multiple overlapping effects of interaction with each other. The main biological meaning of such a response is to objectively determine the volume of the lesion, its local limitation, and create conditions for a subsequent favorable outcome.

The biological significance of the anti-inflammatory response that develops soon after the onset of compensatory activation is to provide mechanisms for limiting inflammation so that the inflammatory reaction is constructive rather than destructive. Anti-inflammatory mediators include IL-4, IL-10, IL-11, IL-13, soluble TNF-a receptor, IL-1 receptor antagonist, and other substances. They reduce the expression of the monocytic major histocompatibility complex class II, stop antigen-presenting activity, and reduce the ability of cells to produce proinflammatory cytokines.

2. Primary systemic reaction. In severe cases of primary damage, proinflammatory and later anti-inflammatory mediators enter the systemic circulation. The biological meaning of proinflammatory mediators entering the systemic bloodstream is to mobilize the body's defense systems not at the local, but at the systemic level. It should be noted that this process is part of the body's normal inflammatory response. Proinflammatory mediators ensure the participation of polymorphonuclear leukocytes, T- and B-lymphocytes, platelets, and coagulation factors in the inflammatory cascade to localize damaged areas. The compensatory anti-inflammatory response reduces the severity of the inflammatory reaction fairly quickly. Organ disorders that occur during this period due to the entry of proinflammatory mediators into the systemic bloodstream are usually transient and quickly leveled out.
3. Massive systemic inflammation. Reduced efficiency of proinflammatory response regulation leads to a pronounced systemic reaction, clinically manifested by signs of systemic inflammatory response syndrome. The following pathophysiological changes may be the basis for these manifestations:
   • progressive endothelial dysfunction leading to increased microvascular permeability;
   • stasis and aggregation of platelets, leading to blockage of the microcirculatory bed, redistribution of blood flow and, following ischemia, post-perfusion disorders;
   • activation of the coagulation system;
   • profound vasodilation, transudation of fluid into the intercellular space, accompanied by redistribution of blood flow and development of shock. The initial consequence of this is organ dysfunction, which develops into organ failure.
4. Excessive immunosuppression. Excessive activation of the anti-inflammatory system is not uncommon. In domestic publications, it is known as hypoergy or anergy. In foreign literature, this condition is called immunoparalysis or "window to immunodeficiency." R. Bon and co-authors suggested calling this condition the syndrome of anti-inflammatory compensatory reaction, putting a broader meaning into its meaning than immunoparalysis. The predominance of anti-inflammatory cytokines does not allow the development of excessive, pathological inflammation, as well as the normal inflammatory process, which is necessary to complete the wound process. It is this reaction of the body that is the cause of long-term non-healing wounds with a large number of pathological granulations. In this case, it seems that the process of reparative regeneration has stopped.

The conducted study of the expression of HLA-DR on the surface of monocytes in patients who suffered severe burn injury showed that in the group of patients where the level of HLA-DR expression was below 30%, and interferon-y was used for treatment, encouraging results were obtained: the condition of patients significantly improved, and immunological tests showed restoration of the level of HLA-DR expression and the ability of monocytes to express TNF-a and IL-6. The data obtained indicate restoration of the immunological balance between the syndrome of systemic inflammatory response and the syndrome of anti-inflammatory compensatory response.

5. Immunological dissonance. The final stage of multiple organ failure is called the "immunological dissonance phase". During this period, both progressive inflammation and its opposite condition - deep syndrome of anti-inflammatory compensatory reaction - can occur.

The absence of a stable balance is the most characteristic feature of this phase. One can observe a fairly rapid change of leading syndromes (inflammatory and compensatory) literally within 24 hours, which indicates the exhaustion of the mechanisms responsible for the parity of these systems. This undoubtedly leads to an imbalance of not only proinflammatory and anti-inflammatory mechanisms, but also of the associated functions of the organs and systems of the body.

According to the authors of the above hypothesis, the balance between pro-inflammatory and anti-inflammatory systems can be disrupted in one of three cases:

• when an infection, severe trauma, bleeding, etc. are so strong that this is quite sufficient for massive generalization of the process, systemic inflammatory response syndrome, multiple organ failure;
• when, due to a previous serious illness or injury, patients are already “prepared” for the development of systemic inflammatory response syndrome and multiple organ failure;
• when the patient’s pre-existing (background) condition is closely related to the pathological level of cytokines.

At the same time, “readiness” for the development of systemic inflammatory response syndrome or multiple organ failure means that the patient, at the time of injury, bleeding, acute pancreatitis, etc., already has a significant pathological component in his “anamnesis” and therefore cannot be considered as an initially healthy patient.

In summing up the discussion of modern concepts of the pathogenesis of sepsis, it is necessary to return to the fundamental concepts of the problem in order to avoid the often ambiguous interpretations and to more clearly define the role and place of each of the concepts in the theoretical concept of generalized forms of infection and in the clinical practice of their treatment.

First of all, we are talking about the systemic inflammatory response. In publications, it is designated as the systemic inflammatory response or systemic inflammatory response syndrome. Depending on the purposes of use and the context of discussion, these designations are given different meanings. The systemic inflammatory response syndrome, or SIRS, is a screening category that allows us to select from a population a group of individuals who have three or four known signs that have the status of defining criteria (SIRSIII or SIRSIV, respectively). It is a mistake to try to supplement the screening criteria with various laboratory, functional or other indicators. It is also incorrect to contrast the two concepts proposed by R. Bon et al. - the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS). The latter has a more capacious and complex semantic content. As a natural "counterweight", this reaction controls the excessive expression of the systemic inflammatory response, being in its deep essence as multifactorial as the latter. It cannot be expressed briefly and clearly as a syndrome, and therefore should not be used as an alternative to the systemic inflammatory response syndrome (SIRS). The compensatory anti-inflammatory response syndrome (CARS) manifests itself indirectly, through the relationship with the multifactorial mechanisms of the systemic inflammatory response, and through one of the isolated phases (forms) of the generalized inflammatory response of the body to infection.

According to the authors' concept, the pathogenesis of clinical manifestations depends on the ratio of the cascade of proinflammatory (for the systemic inflammatory reaction) and anti-inflammatory mediators (for the anti-inflammatory compensatory reaction). The form of clinical manifestation of this multifactorial interaction is the degree of expression of multiple organ failure, determined on the basis of one of the international agreed scales (APACHE, SOFA, etc.). In accordance with this, three gradations of sepsis severity are distinguished: sepsis, severe sepsis, septic shock.

Thus, each of the designations proposed to systematize modern ideas about sepsis has a specific purpose in the general concept.