Systemic inflammatory response syndrome and sepsis

Inflammation is a typical protective reaction to local damage. The evolution of views on the nature of inflammation largely reflects the development of fundamental general biological concepts of the body's response to the effects of damaging factors. Generalization of new data has allowed us to reach a qualitatively new level of understanding of inflammation as a general pathological process underlying the pathogenesis of many critical conditions, including sepsis, severe burn and mechanical trauma, destructive pancreatitis, etc.

The main content of modern concepts of inflammation

Inflammation has an adaptive nature, caused by the reaction of the body's defense mechanisms to local damage. Classic signs of local inflammation - hyperemia, local increase in temperature, swelling, pain - are associated with:

• morpho-functional restructuring of endothelial cells of postcapillary venules,
• coagulation of blood in postcapillary venules,
• adhesion and transendothelial migration of leukocytes,
• complement activation,
• kininogenesis,
• dilation of arterioles,
• degranulation of mast cells.

A special place among inflammation mediators is occupied by the cytokine network, which controls the processes of implementation of immune and inflammatory reactivity. The main producers of cytokines are T-cells and activated macrophages, as well as, to varying degrees, other types of leukocytes, endotheliocytes of postcapillary venules, thrombocytes and various types of stromal cells. Cytokines act primarily in the inflammation focus and in the reacting lymphoid organs, ultimately performing a number of protective functions.

Mediators in small quantities are capable of activating macrophages and platelets, stimulating the release of adhesion molecules from the endothelium and the production of growth hormone. The developing acute phase reaction is controlled by proinflammatory mediators interleukins IL-1, IL-6, IL-8, TNF, as well as their endogenous antagonists such as IL-4, IL-10, IL-13, soluble receptors for TNF, called anti-inflammatory mediators. Under normal conditions, maintaining a balance between pro- and anti-inflammatory mediators creates the prerequisites for wound healing, destruction of pathogenic microorganisms, and maintenance of homeostasis. Systemic adaptive changes in acute inflammation include:

• stress reactivity of the neuroendocrine system,
• fever,
• the release of neutrophils into the circulation from the vascular and bone marrow depots,
• increased leukopoiesis in the bone marrow,
• hyperproduction of acute phase proteins in the liver,
• development of generalized forms of immune response.

The normal concentration of key proinflammatory cytokines in the blood usually does not exceed 5-10 pg/ml. In case of severe local inflammation or failure of the mechanisms limiting its course, some of the cytokines - TNF-a, IL-1, IL-6, IL-10, TCP-beta, y-INF - can enter the systemic circulation, exerting long-distance effects beyond the primary focus. In these cases, their content in the blood can exceed normal values by tens and even hundreds of times. When regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired permeability and function of the capillary endothelium, the onset of DIC syndrome, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. Secondary humoral factors of systemic inflammation include virtually all known endogenous biologically active substances: enzymes, hormones, metabolic products and regulators (more than 200 biologically active substances in total).

The combined effects of mediators form the systemic inflammatory response syndrome (SIRS).

Three main stages began to be distinguished in its development.

Stage 1. Local production of cytokines in response to infection

A special place among inflammation mediators is occupied by the cytokine network, which controls the processes of implementation of immune and inflammatory reactivity. The main producers of cytokines are T-cells and activated macrophages, as well as, to varying degrees, other types of leukocytes, endotheliocytes of postcapillary venules (PCV), thrombocytes and various types of stromal cells. Cytokines act primarily in the inflammation focus and on the territory of the reacting lymphoid organs, and ultimately perform a number of protective functions, participating in the processes of wound healing and protection of body cells from pathogenic microorganisms.

Stage 2: Release of small amounts of cytokines into the systemic circulation

Small amounts of mediators are capable of activating macrophages, platelets, the release of adhesion molecules from the endothelium, and the production of growth hormone. The developing acute phase reaction is controlled by proinflammatory mediators (interleukins IL-1, IL-6, IL-8, tumor necrosis factor (TNF), etc.) and their endogenous antagonists, such as IL-4, IL-10, IL-13, soluble receptors for TNF, etc., which are called antiinflammatory mediators. By maintaining a balance and controlled relationships between pro- and antiinflammatory mediators under normal conditions, prerequisites are created for wound healing, destruction of pathogenic microorganisms, and maintenance of homeostasis. Systemic adaptive changes during acute inflammation include stress reactivity of the neuroendocrine system, fever, the release of neutrophils into circulation from vascular and bone marrow depots, increased leukopoiesis in the bone marrow, hyperproduction of acute phase proteins in the liver, and the development of generalized forms of immune response.

Stage 3. Generalization of the inflammatory reaction

In case of severe inflammation or its systemic failure, some types of cytokines TNF-a, IL-1, IL-6, IL-10, transforming growth factor ß, IFN-y (in viral infections) can penetrate into the systemic circulation and accumulate there in quantities sufficient to implement their long-distance effects. In case of inability of regulatory systems to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired permeability and function of the capillary endothelium, the onset of DIC syndrome, the formation of distant foci of systemic inflammation, and the development of mono- and polyorgan dysfunction. Any disturbances in homeostasis that can be perceived by the immune system as damaging or potentially damaging can apparently also act as factors of systemic damage.

At this stage of the SVR syndrome, from the standpoint of the interaction of pro- and anti-inflammatory mediators, it is possible to conditionally distinguish two periods.

The first, initial period is a period of hyperinflammation, characterized by the release of extremely high concentrations of proinflammatory cytokines, nitric oxide, which is accompanied by the development of shock and early formation of multiple organ failure syndrome (MOFS). However, already at this point, compensatory release of anti-inflammatory cytokines occurs, the rate of their secretion, concentration in the blood and tissues gradually increases with a parallel decrease in the content of inflammation mediators. A compensatory anti-inflammatory response develops, combined with a decrease in the functional activity of immunocompetent cells - a period of "immune paralysis". In some patients, due to genetic determination or reactivity altered by environmental factors, the formation of a stable anti-inflammatory reaction is immediately recorded.

The fundamental differences between systemic inflammation and "classical" inflammation are expressed in the development of a systemic reaction to primary alteration. In this case, proinflammatory mechanisms lose their protective function of localizing damage factors and themselves become the main driving force of the pathological process.

The accumulation of proinflammatory mediators in the blood and the clinical changes that develop with it are considered as SIRS. The formalization of ideas about the nature of inflammation in the form of SIRS was to a certain extent accidental; the concept of sepsis syndrome was introduced in an attempt to more accurately define a group of patients with sepsis during clinical trials. The next step was decisive - working on the task of defining sepsis, the 1991 American College of Chest Physicians/Society Critical Care Medicine consensus conference, based on fundamental research in the field of inflammation, formulated the concept of SIRS, emphasizing its non-specificity.

Pathogenesis of sepsis

A figurative definition of the pathogenesis of sepsis was formulated by I. V. Davydovsky in the 1930s: “An infectious disease is a peculiar reflection of two-sided activity; it has nothing in common with either banal intoxication or with an attack by an “aggressor” using toxic substances.

The causes of infection must be sought in the physiology of the organism, and not in the physiology of the microbe."

In the 21st century (2001) this definition was reflected in the PIRO concept, which suggests 4 links in the pathogenesis of sepsis. Predisposition, including various genetic factors (genetic polymorphism of Toll-like receptors, polymorphism of the coding of the genes IL-1, TNF, CD14, etc.), the presence of concomitant diseases, immunosuppression, age factor, Infection, pathogenicity factors, localization of the lesion, Response of the body to infection - SVR syndrome and Organ dysfunction.

PIRO Concept

Factor	Characteristic
Predisposition	Age, genetic factors, concomitant diseases, immunosuppressive treatment, etc.
Infection (infection)	Localization of the source of infection pathogen
Response	Clinical manifestations of the infectious process (such as body temperature, heart rate, degree of leukocytosis, concentration of procalcitonin, C-reactive protein)
Organ dysfunction	The S0FA scale is used to assess the degree of organ dysfunction.

Experimental studies of the pathophysiological mechanisms of sepsis development at the end of the 20th century led to the conclusion that multiple organ dysfunction in sepsis is a consequence of early and excessive production of proinflammatory cytokines (“excess SIRS”) in response to infection, but the failures of anti-cytokine therapy have called this concept into question.

The “new” pathophysiological concept (“chaos theory”, J Marshall, 2000) suggests a variety of interacting pro- and anti-inflammatory mechanisms “The basis of the systemic inflammatory response is not only and not so much the action of pro- and anti-inflammatory mediators, but oscillatory multisystem interactions, the systemic inflammatory response syndrome in sepsis is not a monotonous reaction, but a symphony of chaos”, and “the determinant of the severity of sepsis is an imbalance in immunity and depression of all endogenous mechanisms of anti-infective defense”.

Activation of systemic inflammation in sepsis begins with activation of macrophages. The mediator between the macrophage and the microorganism (infector) is the so-called Toll-like receptors (TLR), each of the subtypes of which interacts with the pathogenicity factors of a certain group of pathogens (for example, TLR type 2 interacts with peptideglycan, lipoteichoic acid, the cell wall of fungi, etc., TLR type 4 - with the lipopolysaccharide of gram-negative bacteria).

The pathogenesis of gram-negative sepsis is the most well studied. When lipopolysaccharide (LPS) of the cell wall of gram-negative bacteria enters the systemic bloodstream, it binds lipopolysaccharide-binding protein (LPS-BP), which transfers LPS to the CD14 receptors of macrophages, enhancing the macrophage response to LPS by 1000 times. The CD14 receptor in a complex with TLR4 and the MD2 protein through a number of intermediaries causes activation of the synthesis of nuclear factor kappa B (NFKB), which enhances the transcription of genes responsible for the synthesis of proinflammatory cytokines - TNF and IL-1.

At the same time, with a large amount of lipopolysaccharide in the bloodstream, "proinflammatory" mediators between LPS and macrophages play an anti-inflammatory role, modulating the immune response ("chaos theory"). Thus, LPS-SB binds excess LPS in the bloodstream, reducing the transfer of information to macrophages, and the soluble receptor CD14 enhances the transfer of monocyte-bound LPS to lipoproteins, reducing the inflammatory response.

The pathways of modulation of systemic inflammation in sepsis are diverse and practically unstudied, but each of the “pro-inflammatory” links in certain situations becomes an “anti-inflammatory” link in this “chaos”.

A non-specific factor of anti-infective protection is the activation of the complement system, and in addition to the classical and alternative pathways of complement activation, in recent years the lectin pathway has been identified, in which mannose-binding lectin (MBL) binds to a microbial cell in a complex with serine proteases (MBL/MASP), directly cleaving C3, non-specifically activating the complement system.

An increase in the concentration of TNF and IL-1 in the bloodstream becomes the trigger that initiates a cascade of the main links in the pathogenesis of sepsis: activation of inducible NO synthase with an increase in the synthesis of nitric oxide (II), activation of the coagulation cascade and inhibition of fibrinolysis, damage to the collagen matrix of the lungs, increased endothelial permeability, etc.

An increase in the blood concentration of IL-1, TNF activates inducible NO synthase, which leads to an increase in the synthesis of nitric oxide (II). It is responsible for the development of organ dysfunction in sepsis due to the following effects: increased release of free radicals, increased permeability and shunt, changes in enzyme activity, inhibition of mitochondrial function, increased apoptosis, inhibition of leukocyte adhesion, adhesion and aggregation of platelets.

TNF and IL-1, as well as the presence of chemoattractants in the focus, lead to migration of leukocytes to the inflammation focus, their synthesis of adhesion factors (integrins, selectins), secretion of proteases, free radicals, leukotrienes, endothelins, eicosanoids. This leads to damage to the endothelium, inflammation, hypercoagulation, and these effects, in turn, enhance the migration of leukocytes, their adhesion and degranulation, closing the vicious circle.

Lymphopenia, “redifferentiation” of proinflammatory T-helpers 1 into anti-inflammatory T-helpers 2, and increased apoptosis are characteristic of disorders of the lymphocyte lineage of the blood in SIRS.

Disturbances of the hemostasis system in sepsis are also triggered by an increase in the concentration of TNF, IL-1.6 in the blood, damage to the capillary endothelium with an increase in tissue factor IL-6 and tissue factor activate the external mechanism of coagulation by activating factor VII, TNF inhibits natural anticoagulants (protein C, antithrombin III, etc.) and disrupts fibrinolysis [(for example, due to the activation of plasminogen activator inhibitor-1 (PAI-1)].

Thus, in the pathogenesis of sepsis, 3 key links of microcirculation disorders are distinguished: the inflammatory response to infection (adhesion of neutrophils to the capillary endothelium, capillary “leakage”, endothelial damage), activation of the coagulation cascade and inhibition of fibrinolysis.

Systemic inflammatory response and organ dysfunction

Local inflammation, sepsis, severe sepsis and septic shock are links in the same chain in the body's response to inflammation due to bacterial, viral or fungal infection. Severe sepsis and septic shock constitute a significant part of the body's SIRS to infection and develop as a result of the progression of systemic inflammation with dysfunction of organs and their systems.

In general, from the standpoint of modern knowledge, the pathogenesis of organ dysfunction includes 10 consecutive steps.

Activation of systemic inflammation

SIRS is formed against the background of bacterial, viral or fungal invasion, shock of any nature, the phenomenon of ischemia-reperfusion, massive tissue damage, translocation of bacteria from the intestine.

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Activation of initiating factors

The systemic activating factors include coagulation proteins, platelets, mast cells, contact activation systems (production of bradykinin) and complement activation.

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Changes in the microcirculation system

Vasodilation and increased vascular permeability. In local inflammation, the purpose of these changes is to facilitate the penetration of phagocytes to the site of damage. In the case of SV activation, a decrease in systemic vascular tone and damage to the vascular endothelium at a distance from the primary focus are observed.

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Production of chemokines and chemoattractants

The main effects of chemokines and chemoattractants:

• neutrophil margination,
• release of proinflammatory cytokines (TNF-a, IL-1, IL-6) from monocytes, lymphocytes and some other cell populations,
• activation of anti-inflammatory response (possibly)

Margination ("adhesion") of neutrophils to the endothelium

In local inflammation, the chemoattractant gradient orients neutrophils to the center of the lesion, whereas in the development of SV, activated neutrophils diffusely infiltrate perivascular spaces in various organs and tissues.

Systemic activation of monocytes/macrophages.

Damage to the microcirculatory bed

The initiation of SV is accompanied by the activation of free radical oxidation processes and damage to the endothelium with local activation of platelets at the site of damage.

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Tissue perfusion disorders

Due to damage to the endothelium, the occurrence of microthrombosis and decreased perfusion in some areas of microcirculation, blood flow may stop completely.

Focal necrosis

Complete cessation of blood flow in certain areas of the microcirculatory bed is the cause of local necrosis. The organs of the splanchnic basin are especially vulnerable.

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Reactivation of inflammation-initiating factors

Tissue necrosis, which occurs as a result of SV, in turn, stimulates its reactivation. The process becomes autocatalytic, supporting itself, even in conditions of radical sanation of the infectious focus, or stopping of bleeding, or elimination of another primary damaging factor.

Septic shock occurs as a result of excessive vasodilation, increased vascular permeability and myocardial dysfunction due to inhibition of myocardial beta- and alpha-adrenergic receptor activity (limitation of inotropic and chronotropic response), depressive effect of NO on cardiomyocytes, increased concentration of endogenous catecholamines, but decreased effectiveness due to oxidation by superoxidase, decreased density of beta-adrenergic receptors, impaired Ca2+ transport, decreased sensitivity of myofibrils to Ca2+, progressing, septic shock leads to hypoperfusion of organs and tissues, multiple sclerosis and death.

Imbalance of the mediator cascade in sepsis leads to endothelial damage and significant hemodynamic disturbances:

• increase cardiac output,
• decrease in total peripheral vascular resistance,
• redistribution of organ blood flow,
• decrease in myocardial contractility.

Septic shock results from excessive vasodilation, increased vascular permeability and severe hypotension, progressing to organ and tissue hypoperfusion, multiple sclerosis and death.

There are currently no unified, generally accepted criteria for organ-system dysfunction. The most acceptable criteria for everyday clinical practice are those of A Baue et al. and SOFA.

Criteria for organ dysfunction in sepsis (2000)

System, organ	Clinical and laboratory parameters
Cardiovascular system	Clinical and laboratory criteria Systolic BP <90 mm Hg or mean BP <70 mm Hg for 1 hour or more despite correction of hypovolemia
Urinary system	Urine output <0.5 ml/kg/h for 1 hour with adequate volume repletion or creatinine level increases by twice the normal value
Respiratory system	RD/TO, <250, or presence of bilateral infiltrates on radiograph or need for mechanical ventilation
Liver	An increase in bilirubin levels above 20 μmol/l for 2 days or an increase in transaminase activity by two times or more than the norm
Coagulation system	Platelet count <100,000 mm3 or a decrease of 50% from the highest value within 3 days
Metabolic dysfunction	PH <7.3, base deficit >50 mEq/L, plasma lactate content 1.5 times higher than normal
CNS	Less than 15 points on the Glasgow scale

The SOFA (Sepsis organ failure assessment) scale allows determining in quantitative terms the severity of organ-system disorders. A zero value on the SOFA scale indicates the absence of organ dysfunction. Today, the informational significance of the SOFA scale with a minimum of component parameters has the most complete scientific confirmation, which makes it possible to use it in most domestic medical institutions.

Risk factors for the development of organ-system dysfunction:

• old age,
• severe concomitant pathology,
• chronic alcoholism,
• APACHE-II general condition severity index above 15 points,
• genetic predisposition to rapid generalization of systemic inflammation.

The organ that is at the very beginning of the chain of pathological damage in sepsis is usually the lungs. In severe sepsis against the background of peritonitis, ALI occurs on average in 40-60% of cases, and its most severe form - ARDS - is diagnosed in 25-42% of cases. Functional failure of other organs / systems in 83.7% of cases is realized against the background of ALI. In this regard, the most vulnerable organ is the kidneys; renal dysfunction (RD) acts as a component of MOF in 94.8% of patients with severe abdominal sepsis. If oliguria is quite easily eliminated within 1-3 days, then the violation of the nitrogen-excreting function of the kidneys persists for a longer period of time.

Acute liver dysfunction syndrome is registered in one third of patients with abdominal sepsis, less often - in other clinical forms of sepsis. Signs of liver failure almost always develop against the background of already existing functional failure of other organs, most often joining the following combinations of multiorgan syndrome APL + APD or shock + APL + APD.

Impaired consciousness - encephalopathy syndrome - occurs on average by the second day of sepsis development and is more common in elderly and aged patients in conditions of existing MODS syndrome. The severity of functional organ and homeostatic disorders, cumulative effects of arterial hypotension and hypoxemia play a significant role in the development of encephalopathy. Unlike ARDS, the duration of the resulting disorders of consciousness does not exceed 5-6 days.

In its most common form, the sequence of development of PON looks like this: ALI ± SHOCK -» SPD -» Encephalopathy -» Acute liver dysfunction syndrome.

The main feature of organ dysfunction in abdominal sepsis, in contrast to other localizations of the primary focus, is the severity of the multiple organ syndrome and the involvement of a larger number of systems in its structure. Risk factors for septic shock:

• old age,
• severe concomitant pathology of the cardiovascular system,
• chronic liver diseases,
• ARASNE-I index >17 points,
• bacteremia caused by a gram-negative microorganism.

Refractory septic shock and progressive MOD are the main causes of death in patients with sepsis in the acute period of the disease. An increase in the number of organs involved in the MOD process increases the risk of a fatal outcome of the disease, with the infectious process playing a leading role in the development of organ dysfunction. The development of organ dysfunction, additional to the initially existing one, increases the risk of death by 15-20%. The average mortality rate in sepsis with failure in two systems is 30-40%.

Bacteremia and sepsis

Bacteremia is the presence of a bacterial infectious agent in the systemic bloodstream, one of the possible but not obligatory manifestations of sepsis. In the presence of sepsis criteria specified above, the absence of bacteremia should not affect the diagnosis. Even with the most scrupulous observance of blood sampling technique and the use of modern technologies for detecting microorganisms, the frequency of bacteremia registration in the most severe patients, as a rule, does not exceed 45%. Detection of microorganisms in the bloodstream in the absence of clinical and laboratory confirmation of systemic inflammation syndrome in the patient should be regarded as transient bacteremia.

The clinical significance of bacteremia detection may include:

• confirming the diagnosis and determining the etiology of the infectious process,
• evidence of the mechanism of sepsis development (eg, catheter-related infection),
• assessment of the severity of the pathological process (for some situations, for example, when detecting K pneumoniae, P aeruginosa),
• justification of the choice of antibacterial treatment regimen,
• assessing the effectiveness of treatment.

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Clinical and laboratory criteria of systemic inflammation

Clinical and laboratory signs of SIRS are non-specific, its manifestations are characterized by fairly simple diagnostic parameters:

• hyper- or hypothermia of the body,
• tachypnea,
• tachycardia,
• change in the number of leukocytes in the blood.

The diagnosis of SIRS syndrome is based on the registration of at least two of the four clinical and laboratory parameters listed in the table.

Diagnostic criteria for sepsis and septic shock

Pathological process	Clinical and laboratory characteristics
SIRS is a systemic reaction of the body to the effects of various strong irritants (infection, trauma, surgery, etc.)	Characterized by two or more of the following signs: body temperature >38 C or <36 'C; heart rate >90/min; respiratory rate >20/min or hyperventilation (PaCO2 <32 mm Hg); blood leukocytes >12x10 9 /ml, or <4x10 9 /ml or immature forms >10%
Sepsis - SIRS for microbial invasion	Presence of a foci of infection and 2 or more signs of systemic inflammatory response syndrome
Severe sepsis	Sepsis, combined with organ dysfunction, hypotension, and tissue perfusion disorders. Manifestations of the latter include increased lactate concentration, oliguria, and acute impairment of consciousness.
Septic shock	Severe sepsis with signs of tissue and organ hypoperfusion, arterial hypotension, which cannot be eliminated with infusion therapy
Multiple organ dysfunction/failure syndrome (MODS)	Dysfunction of 2 or more systems
Refractory septic shock	Arterial hypotension persists despite adequate infusion; use of inotropic and vasopressor support

Despite the imperfection of the SIRS criteria (low specificity), their sensitivity reaches 100%. Therefore, the main practical meaning of diagnosing the SIRS syndrome is to identify a group of patients who cause concern for the clinician, which requires a rethinking of the treatment tactics and proper diagnostic search necessary for timely and adequate therapy.

From a general biological standpoint, sepsis is one of the clinical forms of SIRS, where a microorganism acts as a factor initiating damage. Thus, sepsis is a pathological process based on the body's reaction in the form of generalized (systemic) inflammation to an infection of various origins (bacterial, viral, fungal).

The result of the clinical interpretation of this view on the pathogenesis of sepsis was the classification and diagnostic criteria proposed by the consensus conference of the American College of Chest Physicians and the Society of Critical Care Specialists (ACCP/SCCS).

Low specificity of SIRS criteria has led to the development of approaches to differential diagnostics of infectious and non-infectious genesis of the syndrome. To date, the best diagnostic test for this purpose is the determination of procalcitonin content in the blood using direct measurement or a semi-quantitative rapid test. The concentration of procalcitonin in the blood increases with bacterial or fungal sepsis

Diagnosis of sepsis

Currently, it is possible to diagnose secondary immunodeficiency and its degree, as well as dynamically assess the state of the immune system. However, there are no final criteria.

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Requirements for indicators used for diagnostics

• be accessible in practice,
• objectively reflect the state of various links of the immune system,
• respond dynamically to changes in the patient's clinical condition during treatment.

Laboratory tests recommended for the detection of immunodeficiency in critically ill patients:

• determination of the absolute number of lymphocytes, HLA-DR monocytes and apoptotic lymphocytes,
• the content of immunoglobulins M, C, A in the blood,
• phagocytic activity of neutrophils.

Criteria for the diagnosis of immunodeficiency^

• absolute lymphocyte count in peripheral blood less than 1.4x10 ⁹ /l,
• the number of HLA-DR-positive monocytes is less than 20%, apoptotic lymphocytes - more than 10%,
• a decrease in the blood content by more than 1.5 times from the norm (0.7-2.1 g/l) and below the norm (9-15 g/l), the phagocytic index of neutrophils in the early stages of phagocytosis (PI 5 min - below 10%).

Calculation of the absolute number of lymphocytes in a complete blood count is available in every clinic and is very informative. A decrease in lymphocytes below 1.0x10 ⁹ /l indicates immunodeficiency. Determination of HLA-DR-positive monocytes and apoptotic lymphocytes (CD 95) is also informative, but the method is less accessible, since it is carried out using flow cytofluorometry. Determination of the content of immunoglobulins in the blood (using test systems) and the phagocytic activity of neutrophils (latex test, microscopy) are considered quite simple. Thus, secondary immunodeficiency in the composition of PON can be diagnosed based on three criteria out of five available. A significant decrease in lymphocytes (less than 1.0x10 ⁹ /l) and immunoglobulins (IgM 1.5 times below normal and IgG below normal) most likely indicates secondary immunodeficiency.

Determination of cytokine concentration in blood serum is not widely used in clinical practice, since none of the known mediators can be considered universal. Numerous studies show that the release of proinflammatory mediators is differentiated. The content of TNF-a, IL-1, 6, 8 in the blood of healthy donors averages from 0 to 100 pg / ml. A concentration of 3000-4000 pg / ml is considered lethal. The content of TNF-a is associated with early events (shock), IL-8 - with later clinical manifestations (DIC, severe hypoxia, death). High concentration of IL-6 is characteristic of the fulminant development of septic shock and correlates with mortality. Patients with septic shock are not considered a homogeneous group by cytokine content. There are reports of a relationship between consistently high concentrations of TNF, IL-1, interferon-a and mortality. There may be no correlation between high cytokine content and shock. In gram-negative and fungal infections, the content of granulocyte colony-stimulating factor in the blood increases. High concentrations are found in patients with neutropenia, and they correlate with the degree of temperature increase.

The content of acute-phase proteins (procalcitonin and C-reactive protein) is associated with the degree of inflammatory response and serves for monitoring during treatment. The concentration of C-reactive protein (more than 50 mg / l) with a sensitivity of 98.5% and a specificity of 45% indicates the development of sepsis. The content of procalcitonin of 1.5 ng / ml and more allows identifying sepsis, with a sensitivity of 100% and a specificity of 72%. In patients with malignant neoplasm of the esophagus, an increase in the concentration of C-reactive protein (10-20 times, before the operation - <10 mg / l) and procalcitonin (median 2.7 ng / ml, before the operation - <0.5 ng / ml) is noted 1-3 days after esophagectomy. Sepsis was not diagnosed in any patient, and an increase in the content of C-reactive protein and procalcitonin is considered a response of the body to surgical trauma. Despite its great diagnostic potential, procalcitonin is not used as a marker of sepsis in patients with SIRS. This test is used to exclude the diagnosis of sepsis and monitor the effectiveness of treatment.

A new diagnostic marker of inflammation may be the trigger receptor expressed on myeloid cells (TREM-1). The content of soluble TREM-1 in BAL fluid of patients with bacterial or fungal pneumonia on mechanical ventilation exceeds 5 pg/ml (sensitivity - 98%, specificity - 90%), and the concentrations of procalcitonin and C-reactive protein in patients with and without pneumonia do not differ.

Immunotherapy for Sepsis

Critical condition, severe infection and PON are inextricably linked. Data on pathophysiological mechanisms allow us to speak about the advisability of including drugs that modulate and correct the systemic inflammatory response in the complex therapy.

Posttraumatic immune disorders include hyperactivation of inflammatory processes and deep depression of cell-mediated immune functions. Immunomodulation restores the suppressed immune response without increasing hyperinflammation. The strategy of immunomodulation is to prevent the development of PON by blocking or weakening the manifestations of SIRS. Immunomodulation should be carried out as soon as possible after injury. Its goal is to protect lymphocytes, macrophages, granulocytes, endothelial cells from hyperactivation and functional exhaustion. Immunological disorders in trauma and sepsis cannot be caused by a change in the concentration of a single cytokine. The action of cytokines can be synergistic or antagonistic, and the effects repeatedly cross each other.

Immunotherapy solves two problems:

1. Removal of infectious agents and their toxic products. This reduces the role of the infectious agent in maintaining the systemic inflammatory response.
2. Reducing the manifestation of the systemic inflammatory response caused by trauma and severe infection to prevent hemodynamic and organ dysfunction and the development of multiple sclerosis.

Main criteria of immunomodulatory therapy (according to BaM E, 1996)

• prevention of excessive stimulation of macrophages by neutralizing circulating exo- and endotoxins with high doses of polyvalent immunoglobulins and soluble complement receptors,
• global short-term (<72 h) suppression of inflammatory activity of macrophages and neutrophils - granulocyte colony-stimulating factor, pentoxifylline, IL-13,
• restoration of cell-mediated immunity to prevent post-traumatic functional paralysis - indomethacin, interferon-y.

Areas of application of immunocorrection:

• humoral, cellular, non-specific immunity,
• cytokine network,
• coagulation system.

In humoral immunity, the priority is considered to be increasing the content of immunoglobulins of class M and C (in the processes of opsonization and killing of infectious agents, activation of phagocytosis and neutralization of complement), as well as stimulation of B-lymphocytes.

For cellular immunity, it is necessary to restore the normal ratio between T-helpers and T-suppressors (characterized by the predominance of suppressors) and activate NK cells.

Non-specific immunity is the first barrier standing in the way of infection. Its tasks are to restore the phagocytic activity of neutrophils and macrophages, reduce the hyperproduction of pro-inflammatory cytokines (TNF and IL-1) by macrophages, and neutralize activated membrane-destroying components of complement (C5-9).

Features characteristic of cytokines

• a minor role in normal homeostasis,
• produced in response to exogenous stimuli,
• are synthesized by many types of cells (lymphocytes, neutrophils, macrophages, endothelial cells, etc.),
• damage the immunoregulatory and metabolic functions of the body,
• suppression of excess cytokine release is necessary, but nothing more.

Hyperproduction of such proinflammatory cytokines as TNF and IL-1 leads to increased vascular permeability, hyperactivation of lymphocytes, and the formation of hypercatabolism. IL-8 promotes the migration of granulocytes from the vascular bed to the interstitial space. Increased concentrations of anti-inflammatory cytokines (IL-4, 10, soluble TNF receptor, IL-1 receptor antagonist) lead to the development of anergy to infection, or so-called immune paralysis. It is very difficult to restore the optimal balance between pro- and anti-inflammatory cytokines, as well as to prevent the persistence of high concentrations of TNF and IL-6 in the area of cytokine network correction.

In the coagulation system, it is necessary to achieve suppression of thrombus formation and activate fibrinolysis. In parallel, apoptosis processes in endothelial cells are reduced.

According to the mechanism of action, treatment can be immunoreplacement (replacing immunodeficiency) or immunocorrective (modulation of immune links - stimulation or suppression).

The patient's critical condition leads to the development of an acute form of immunodeficiency (pronounced shifts in the immune system quickly replace each other). The studied cases encountered in domestic literature are classified as chronic immunodeficiencies (shifts in the immune system are not so significant and do not affect the general condition of the patient, which cannot be called critical). However, not all immunocorrective drugs used in this case are considered effective, and the studies are not considered properly conducted.

Criteria for drugs used for immunocorrection

• proven effectiveness,
• safety,
• purposeful action (presence of a target),
• speed of action,
• dose-dependent effect,
• clear control parameters.

Prescribing a drug to a patient in a serious condition receiving powerful drugs should have reasoned indications and evidence of its effectiveness. The main requirement is the absence of side effects. An immunocorrective drug cannot act on all links of the immune system at once. Its effectiveness is achieved due to the targeted action on a specific target in pathogenesis. Speed of action and dose-dependence of the effect are universal requirements for drugs used in intensive care. The effect of the treatment is necessary in a few days, and not 2-3 weeks after its completion. An indicator of the effectiveness of the therapy, in addition to the general clinical assessment of the severity of the condition (APACHE, SOFA scales, etc.), is considered to be changes in the pathogenetic link, which is the main effect of immunocorrection. These changes are diagnosed using available laboratory research methods.

Possible directions for correction of the main pathophysiological aspects of systemic inflammation in critical conditions and sepsis are presented in the table.

Possible directions for correction of the main pathophysiological aspects of systemic inflammation in critical conditions and sepsis

Target	Agent	Mechanism of action
Endotoxin	Monoclonal antibodies to endotoxin	Opsonization
LPS-LPS-binding protein complex	Antibodies to L PS	Reduction of LPS-induced macrophage activation
TNF	Monoclonal antibodies to TNF soluble receptor to TNF	TNF binding and inactivation
IL-1	IL-1 receptor antagonist	Competing with the IL-1 receptor
Cytokines	Glucocorticoids, pentoxifylline	Blockade of cytokine synthesis
Platelet activating factor	Platelet activating factor antagonist, phospholipase A2 inhibitor, platelet activating factor acetylhydrolase	Competition with the receptor to PAF, reduction of the content of PAF and leukotrienes
Thromboxane	Ketoconazole	Inhibition of thromboxane synthesis
NО	NO synthesis inhibitor	Inhibition of NO synthesis
Free radicals	Acetylcysteine, sodium selenite, vitamins C and E, catalase, superoxide dismutase	Inactivation and reduction of free radical emissions
Arachidonic acid metabolites	Indomethacin, ibuprofen leukotriene receptor antagonist	Inhibition of cyclo- and lipoxygenase pathways, blockade of prostaglandin receptors
Coagulation system	Antithrombin III, activated protein C	Anticoagulation, reduction of platelet activation, reduction of proinflammatory cytokines, effect on neutrophils
Cytokine network humoral immunity	Interferon-y, granulocyte colony-stimulating factor, immunoglobulin	Restoration of antibody deficiency, restoration of neutrophil activity, reduction of the concentration of proinflammatory cytokines

Currently, clinical trials are being conducted on the use of immunotherapy in severe infections and critical conditions. The effectiveness of enriched immunoglobulin (pentaglobin) and activated protein C [drotrecogin-alpha activated (zigris)] is considered proven. Their action is associated with the replacement of immunodeficiency in the humoral immunity (pentaglobin) and the coagulation system [drotrecogin-alpha activated (zigris)] - a direct immunotherapeutic effect. These drugs also have an immunomodulatory effect on the cytokine network, nonspecific and cellular immunity. Clinical studies have proven the effectiveness of enriched immunoglobulin (5 ml / kg, 28 ml / h, 3 days in a row) in neutropenia, immunological anergy, neonatal sepsis, in the prevention of polyneuropathy of critical conditions. Activated protein C [24 mcg/(kg h), as a continuous infusion, for 96 h] is effective in severe sepsis.

Interferon-y restores the expression of HLA-DR by macrophages and TNF production. The use of antibodies to activated complement (C5a) reduces the incidence of bacteremia, prevents apoptosis, and increases survival. The use of antibodies to the factor inhibiting macrophage migration protects rats from peritonitis. Nitric oxide is an endogenous vasodilator synthesized by KGO synthetase from L-arginine. Its hyperproduction causes hypotension and myocardial depression in septic shock, and the use of inhibitors (KT-methyl-L-arginine) restores blood pressure. During the activation and degranulation of neutrophils, a large number of free radicals are formed, causing tissue damage in systemic inflammation. The possibilities of endogenous antioxidants (catalase and superoxide dismutase) to neutralize free radicals in sepsis are being studied.

The table summarizes the results of multicenter, double-blind, placebo-controlled, randomized studies on the effectiveness of immunocorrective therapy for sepsis and MOF.

Results of multicenter, double-blind, placebo-controlled, randomized studies on the effectiveness of immunocorrective therapy for sepsis and MOF

Preparation	Research result	Author, date
Granulocyte colony-stimulating factor (filgrastim)	Does not reduce 28-day mortality	Rott R.K, 2003
Antibodies to endotoxin (E 5)	Do not reduce mortality in patients without shock	Bone R.C., 1995
Antibodies to total endotoxin of enterobacteria	Do not reduce mortality	Albertson T.E, 2003
Pentoxifylline	Reduction in mortality - 100 newborns	Lauterbach R., 1999
Glucocorticoids	Use "small doses" Stabilization of hemodynamics	Appape D, 2002, Keh D 2003
IL-1 receptor antagonist	Does not reduce lethality	Opal SM 1997
Antibodies to TNF	Does not reduce 28-day mortality	Abraham E. 1997, 1998
PAF receptor antagonist	Does not reduce lethality	Dhamaut JF 1998
COX inhibitors	Do not reduce mortality	Zen IF, 1997
Antithrombin III	Does not reduce lethality	Warren B.L. 2001
Ketoconazole	Does not reduce lethality	The ARDS network, 2000
Immunoglobulins (G+M)	Significantly reduce mortality	Alejandria MM 2002
Activated Protein C	Reduces lethality	Bernard G. R., 2004
Interferon-y Antibodies to C5a Antibodies to FUM Inhibitors N0 Antioxidants	Effective in animal models	Hotchkiss RS 2003

By studying the pathogenesis of critical conditions and understanding the role of the immune system in these processes, criteria for diagnosing immunodeficiency in the context of PON will be developed and effective drugs for its correction will be proposed.