immune therapy. Immunomodulatory therapy. Immunostimulatory therapy. Types of immunostimulating therapy. The use of immunomodulators. With repeated use of immunomodulators, the spectrum of their action is preserved, the effectiveness increases.

Interest in immunostimulatory therapy, which has a long history, has increased dramatically in recent years and is associated with the problems of infectious pathology and oncology. Specific treatment and prevention based on vaccination are effective for a limited number of infections.

With infections such as intestinal and influenza, the effectiveness of vaccination remains insufficient. The high percentage of mixed infections, the polyetiology of many make the creation of specific preparations for immunization against each of the possible pathogens unrealistic. The introduction of sera or immune lymphocytes is effective only in the early stages of the infectious process. In addition, the vaccines themselves in certain phases of immunization are able to suppress the body's resistance to infections. It is also known that due to the rapid increase in the number of pathogens with multiple resistance to antimicrobial agents, the high frequency of associated infections, the sharp increase in immunization can suppress the body's resistance to L-forms of bacteria and the significant number of serious complications, effective antibiotic therapy is becoming increasingly difficult. The course of the infectious process is complicated, and the difficulties of therapy are significantly aggravated when the immune system and nonspecific defense mechanisms are affected. These disorders can be genetically determined or occur secondarily under the influence of various factors. All this makes the problem of immunostimulating therapy urgent. With the widespread introduction of asepsis, which prevents the introduction of microorganisms into the surgical wound, science-based infection prevention in surgery began. Only eighty-six years have passed, and the theory of infection in surgery has come a long and difficult way. The discovery and widespread use of antibiotics provided reliable prevention of suppuration of surgical wounds. Clinical immunology is a young branch of medical science, but already the first results of its application in prevention and treatment open up broad prospects. The limits of clinical immunology are still difficult to fully foresee, but now we can say with confidence that in this new branch of science, physicians are gaining a powerful ally in the prevention and treatment of infections.

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Introduction

Interest in immunostimulatory therapy, which has a long history, has increased dramatically in recent years and is associated with the problems of infectious pathology and oncology.

Specific treatment and prevention based on vaccination are effective for a limited number of infections. With infections such as intestinal and influenza, the effectiveness of vaccination remains insufficient. The high percentage of mixed infections, the polyetiology of many make the creation of specific preparations for immunization against each of the possible pathogens unrealistic. The introduction of sera or immune lymphocytes is effective only in the early stages of the infectious process. In addition, the vaccines themselves in certain phases of immunization are able to suppress the body's resistance to infections. It is also known that due to the rapid increase in the number of pathogens with multiple resistance to antimicrobial agents, the high frequency of associated infections, the sharp increase in immunization can suppress the body's resistance to L-forms of bacteria and the significant number of serious complications, effective antibiotic therapy is becoming increasingly difficult.

The course of the infectious process is complicated, and the difficulties of therapy are significantly aggravated when the immune system and nonspecific defense mechanisms are affected. These disorders can be genetically determined or occur secondarily under the influence of various factors. All this makes the problem of immunostimulating therapy urgent.

With the widespread introduction of asepsis, which prevents the introduction of microorganisms into the surgical wound, science-based infection prevention in surgery began.

Only eighty-six years have passed, and the theory of infection in surgery has come a long and difficult way. The discovery and widespread use of antibiotics provided reliable prevention of suppuration of surgical wounds.

Clinical immunology is a young branch of medical science, but already the first results of its application in prevention and treatment open up broad prospects. The limits of clinical immunology are still difficult to fully foresee, but now we can say with confidence that in this new branch of science, physicians are gaining a powerful ally in the prevention and treatment of infections.

1. Mechanisms of immunological defense of the body

The beginning of the development of immunology dates back to the end of the 18th century and is associated with the name of E. Jenner, who was the first to apply, on the basis of only practical observations, subsequently a theoretically substantiated method of vaccination against smallpox.

The fact discovered by E. Jenner formed the basis for further experiments by L. Pasteur, which culminated in the formulation of the principle of prevention from infectious diseases - the principle of immunization with weakened or killed pathogens.

The development of immunology for a long time took place within the framework of microbiological science and concerned only the study of the body's immunity to infectious agents. In this way, great success has been achieved in uncovering the etiology of a number of infectious diseases. A practical achievement was the development of methods for diagnosing, preventing and treating infectious diseases, mainly by creating various kinds of vaccines and sera. Numerous attempts to elucidate the mechanisms that determine the resistance of the organism against the pathogen culminated in the creation of two theories of immunity - phagocytic, formulated in 1887 by I. I. Mechnikov, and humoral, put forward in 1901 by P. Ehrlich.

The beginning of the 20th century is the time of the emergence of another branch of immunological science - non-infectious immunology. As the starting point for the development of infectious immunology were the observations of E. Jenner, so for non-infectious - the discovery by J. Bordet and N. Chistovich of the fact of the production of antibodies in the animal body in response to the introduction of not only microorganisms, but in general foreign agents. Non-infectious immunology received its approval and development in the doctrine of cytotoxins created by I. I. Mechnikov in 1900 - antibodies against certain tissues of the body, in the discovery by K. Landsteiner in 1901 of human erythrocyte antigens.

The results of the work of P. Medawar (1946) expanded the scope and drew close attention to non-infectious immunology, explaining that the process of rejection of foreign tissues by the body is also based on immunological mechanisms. And it was the further expansion of research in the field of transplantation immunity that attracted the discovery in 1953 of the phenomenon of immunological tolerance - the non-response of the body to the introduced foreign tissue.

Thus, even a brief digression into the history of the development of immunology makes it possible to assess the role of this science in solving a number of medical and biological problems. Infectious immunology, the progenitor of general immunology, has now become only its branch.

It became obvious that the body very accurately distinguishes between “own” and “foreign”, and the reactions that arise in it in response to the introduction of foreign agents (regardless of their nature) are based on the same mechanisms. The study of the totality of processes and mechanisms aimed at maintaining the constancy of the internal environment of the body from infections and other foreign agents - immunity, underlies the immunological science (V.D. Timakov, 1973).

The second half of the twentieth century was marked by the rapid development of immunology. It was during these years that the selection-clonal theory of immunity was created, the regularities of the functioning of various parts of the lymphoid system as a single and integral system of immunity were discovered. One of the most important achievements of recent years has been the discovery of two independent effector mechanisms in the specific immune response. One of them is associated with the so-called B-lymphocytes, which carry out a humoral response (the synthesis of immunoglobulins), the other is associated with a system of T-lymphocytes (thymus-dependent cells), the result of which is a cellular response (accumulation of sensitized lymphocytes). It is especially important to obtain evidence of the existence of the interaction of these two types of lymphocytes in the immune response.

The research results suggest that the immunological system is an important link in the complex mechanism of adaptation of the human body, and its action is primarily aimed at maintaining antigenic homeostasis, the violation of which may be due to the penetration of foreign antigens into the body (infection, transplantation) or spontaneous mutation.

But, as studies of recent years have shown, the division of immunity into humoral and cellular is very conditional. Indeed, the influence of the antigen on the lymphocyte and the reticular cell is carried out with the help of micro- and macrophages that process immunological information. At the same time, the reaction of phagocytosis, as a rule, involves humoral factors, and the basis of humoral immunity is cells that produce specific immunoglobulins. The mechanisms aimed at the elimination of a foreign agent are extremely diverse. In this case, two concepts can be distinguished - “immunological reactivity” and “nonspecific protective factors”. The first refers to specific reactions to antigens, due to the highly specific ability of the body to respond to foreign molecules. However, the protection of the body from infections also depends on the degree of permeability of the skin and mucous membranes to pathogenic microorganisms, and the presence of bactericidal substances in their secretions, the acidity of the gastric contents, and the presence of enzyme systems such as lysozyme in the biological fluids of the body. All these mechanisms are classified as non-specific protection factors, since there is no special response and they all exist regardless of the presence or absence of the pathogen. Some special position is occupied by phagocytes and the complement system. This is due to the fact that, despite the nonspecificity of phagocytosis, macrophages are involved in the processing of the antigen and in the cooperation of T- and B-lymphocytes during the immune response, that is, they participate in specific forms of response to foreign substances. Similarly, complement production is not a specific response to an antigen, but the complement system itself is involved in specific antigen-antibody reactions.

2. Immunomodulatingfunds

Immunomodulating agents are preparations of a chemical or biological nature that are capable of modulating (stimulating or suppressing) immune responses as a result of influencing immunocompetent cells, their migration processes, or the interaction of such cells or their products.

2.1 Polysaccharides

The number of reports on the study of various lipopolysaccharides (LPS) continues to grow rapidly. The LPS of gram-negative bacteria, the shell of which contains up to 15-40% LPS, is studied especially intensively. Polysaccharide preparations, recently levamisole, are of great interest among the means of nonspecific immunostimulating therapy.

Most LPS are unacceptable for clinical use due to their high toxicity and abundance of side effects, but they are a valuable tool for immunological analysis. But LPS are very active and have a wide range of immunomodulatory effects, and therefore there is a constant search for new, less toxic LPS. Proof of this is the synthesis of salmosan, which is a polysaccharide fraction of the samotic O-antigen of typhoid bacteria. It has low toxicity, practically does not contain proteins and lipids. In experiments on mice, it has been proven that when administered parenterally, salmosan stimulates the proliferation and differentiation of stem cells, stimulates the formation of antibodies, the phagocytic activity of leukocytes and macrophages, increases the titer of lysozyme in the blood, and stimulates nonspecific resistance to infections.

Recent studies prove that polysaccharides and polysaccharide complexes are not the only components of a bacterial cell that can stimulate immunity.

But of the bacterial polysaccharides in medicine, pyrogenal and prodigiosan are currently more widely used.

Pyrogenal: a drug that has long been included in the arsenal of non-specific immunostimulating therapy. It causes short-term (several hours) leukopenia, followed by leukocytosis, and increases the phagocytic function of leukocytes. In the organization of nonspecific protection against infection, the main significance of pyrogenal is associated with the activation of phagocytosis. Like other LPS, pyrogenal exhibits adjuvant properties, increasing the immune response to various antigens. Mobilization of phagocytic mechanisms, stimulation of the formation of antibodies, humoral non-specific protective factors may be the reason for the increase in anti-infective resistance under the influence of pyrogenal. But it depends on the time of exposure to pyrogenal in relation to the moment of infection, dose, purity of administration.

But in acute infectious diseases, pyrogenal is not used because of the powerful pyrogenic effect, although fever increases the body's resistance to a number of infections, causing favorable metabolic and immunological changes.

The main clinical area of ​​using pyrogenal as a means of non-specific immunostimulating therapy is chronic infectious and inflammatory diseases. Significant experience has been accumulated in the use of pyrogenal in the complex therapy of tuberculosis (together with antibacterial drugs): it accelerates the closure of decay cavities in patients who have been diagnosed with pulmonary tuberculosis for the first time, and improves the clinical course of the disease in patients previously unsuccessfully treated only with antibacterial agents. The greatest activity is noted in the cavernous, infiltrative form of pulmonary tuberculosis. The ability of pyrogenal to stimulate antibiotic therapy is apparently associated with anti-inflammatory, sensitizing, fibrinolytic effects, with increased regenerative processes in tissues. The prospects for the use of pyrogenal in oncology are evidenced by experimental observations: the drug reduces grafting and delays tumor growth, enhances the antitumor activity of radiation and chemotherapy. Information on the use of pyrogenal as an anti-allergic agent is very contradictory. It is effective in some skin diseases. But it enhances the manifestation of anaphylactic shock, the phenomenon of Arthus and Schwartzman. Being an interferon inducer, pyrogenal reduces resistance to viral infections - a direct contraindication in diagnosing influenza.

Prodigiosan: the most striking and important effect is a non-specific increase in the body's resistance to infections. In addition to high efficiency in generalized infections, prodigiosan also has an effect in local purulent-inflammatory processes, accelerates the elimination of infection, necrotic decay products, resorption of inflammatory exudate, healing of damaged tissues, and helps to restore organ functions.

Most importantly, prodigiosan increases the effect of antibiotics when using subeffective doses of antibiotics and in infections caused by antibiotic-resistant strains.

Prodigiosan, like other LPS, does not have a direct effect on microorganisms. The increase in resistance to infections is entirely due to the anti-infection mechanisms of the macroorganism. The increase in resistance occurs four hours after injection, reaches a maximum in a day, then decreases. but remains at a sufficient level for a week.

The action of prodigiosan is based on:

a) on vigorous mobilization of the phagocytic activity of macrophages and leukocytes;

b) to increase their number;

c) on strengthening the absorption and digestion functions;

d) on an increase in the activity of lysosomal enzymes;

e) on the fact that the maximum phagocytic activity of leukocytes is retained longer than leukocytosis: the number of leukocytes in peripheral blood returns to normal on the first or second day, and activity - only by the third day;

e) on an increase in the opsonizing action of blood serum.

Prodigiosan's pathway of action:

stimulation of macrophages by prodigiosan - monokines - lymphocytes - lymphokines - activation of macrophages.

There is little information on the effect of prodigiosan on the T- and B-systems of immunity.

Prodigiosan has a positive effect on the clinical course of a number of diseases and improves immunological parameters (bronchopulmonary diseases, tuberculosis, chronic osteomyelitis, aphthous stomatitis, dermatosis, tonsillitis, treatment and prevention of respiratory viral infections in children).

For example, the use of prodigiosan in the early stages of acute pneumonia with a sluggish course is a means of preventing the process from becoming chronic; prodigiosan helps to reduce the severity of allergic reactions, the incidence of tonsillitis by four times in patients with chronic tonsillitis, reduces the incidence of acute respiratory diseases by two to three times.

2.2 Nucleic acid preparations and synthetic polynucleotides

In recent years, interest in polyanionic adjuvants has increased due to the intensive search for immunostimulants.

For the first time, nucleic acids began to be used in 1882 at the initiative of Gorbachevsky for infectious diseases of strepto- and staphylococcal origin. In 1911, Chernorutsky found that under the influence of yeast nucleic acid, the number of immune bodies increases.

Nucleinate sodium: increases phagocytic activity, activates poly- and mononuclear cells, increases the effectiveness of tetracyclines in mixed infections caused by staphylococcus and Pseudomonas aeruginosa. With prophylactic administration, sodium nucleinate also causes an antiviral effect, since it has interferonogenic activity.

Sodium nucleinate accelerates the formation of vaccination immunity, increases its quality, and reduces the dose of the vaccine. This drug has a positive effect in the treatment of patients with chronic parotitis, peptic ulcer, various forms of pneumonia, chronic pneumonia, bronchial asthma. Sodium nucleinate increases the content of RNA and protein in macrophages by 1.5 times and glycogen by 1.6 times, increases the activity of lysosomal enzymes, and therefore increases the completion of phagocytosis by macrophages. The drug increases the content of lysozyme and normal antibodies in humans, if their level has been reduced.

A special place among nucleic acid preparations is occupied by immune RNA macrophages, which is an information RNA that introduces an antigen fragment into the cell, therefore, there is a non-specific stimulation of immunocompetent cells with nucleotides.

Non-specific stimulants are synthetic double-stranded polynucleotides, which stimulate antibody formation, increase the antigenic effect of non-immunogenic doses of an antigen that has antiviral properties associated with interferonogenic activity. Their mechanism of action is complex and not well understood. Double-stranded RNA is included in the system of regulation of protein synthesis in the cell, actively interacting with the cell membrane.

But the high cost of drugs, their lack of effectiveness, the presence of side effects (nausea, vomiting, lowering blood pressure, increased body temperature, impaired liver function, lymphopenia - due to direct toxic effects on cells), lack of use patterns make the use of drugs limited.

2.3 Pyrimidine and purine derivatives

Pyrimidine and purine derivatives are increasingly used as agents that increase the body's resistance to infections. A great merit in the study of pyrimidine derivatives belongs to N. V. Lazarev, who more than 35 years ago was the first to come to the idea of ​​the need for agents that accelerate regeneration processes. Pyrimidine derivatives are interesting in that they have low toxicity, stimulate protein and nucleic metabolism, accelerate cell growth and reproduction, and cause anti-inflammatory effects. Methyluracil, which stimulates leukopoiesis and erythropoiesis, is the most widely used as a stimulant of anti-infectious resistance. Pyrimidine derivatives are able to prevent a decrease in the phagocytic activity of leukocytes, which occurs under the influence of antibiotics, cause the induction of interferon synthesis, increase the level of immunization, the level of normal antibodies. The mechanism of their action as immunogenesis stimulators is apparently associated with their inclusion in protein and nucleic metabolism, which causes a polyvalent effect on immunogenesis and regeneration processes.

The clinic is used in the treatment of tuberculosis, chronic pneumonia, leprosy, erysipelas, burn disease. For example, the inclusion of methyluracil in the complex therapy of dysentery, which contributes to the normalization of natural resistance indicators (complement, lysozyme, serum β-lysine, phagocytic activity).

Purine derivatives are also immunostimulants: meradin, 7-isoprinasine, 9-methyladenine.

Isoprinazine is one of the new immunostimulants, which belongs to immunomodulators. The drug has a wide range of therapeutic effects. It changes the immunological response at different stages: stimulates the activity of macrophages, enhances proliferation, cytotoxic activity of lymphocytes, enhances the number and activity of phagocytosis. It is known that isoprinazine does not affect the function of normal polymorphonuclear leukocytes.

2.4 Imidazole derivatives

This group of immunostimulants includes levamisole, dibazol and cobalt-containing imidazole derivatives.

Levamisole: It is a white powder, highly soluble in water, low toxicity. The drug is an effective antihelminthic agent. The effect of levamisole on immunological processes was discovered later. Levamisole stimulates mainly cellular immunity. It is the first drug to mimic the hormonal regulation of the immune system, that is, the modulation of regulatory T cells. The ability of levamisole to imitate thymus hormone is provided by its imidazole-like effect on the level of cyclic nucleotides in lymphocytes. It is possible that the drug stimulates thymopoietin receptors. The drug favorably affects the immunological status by restoring the effector functions of peripheral T-lymphocytes and phagocytes, stimulating the maturation of T-lymphocyte precursors, similar to the action of thymus hormones. Levamisole is a powerful differentiation inducer. The drug causes a rapid effect (after 2 hours when taken orally). Increasing the activity of macrophages with levamisole plays a large role in the ability of the drug to increase the immunological properties of the body.

Treatment with levamisole leads to lessening, shortening and reducing the intensity of the infectious process. The drug reduces inflammation in acne, restores the reduced function of T-cells. There is evidence of the importance of levamisole in the treatment of cancer. It prolongs the duration of remission, increases survival and prevents tumor metastasis after tumor removal or radiation and chemotherapy. How are these effects realized? This depends on the increase in the activity of cellular immunity by levamisole in cancer patients, on the strengthening of immune control in which T-lymphocytes and macrophages stimulated by levamisole play a role. Levamisole does not increase the immune response above the normal level for a person, and it is especially effective in cancer patients with immunodeficiency states. Adverse reactions of levamisole: gastrointestinal disorders in 90% of cases, CNS excitation, flu-like condition, allergic skin rashes, headache, weakness.

Dibazol: a drug that has the properties of an adaptogen - stimulates glycolysis, protein synthesis, nucleic acids. It is used more often with a preventive purpose, and not with a curative one. Reduces susceptibility to infections caused by staphylococcus, streptococcus, pneumococcus, salmonella, rickettsia, encephalitis viruses. Dibazol, when administered to the body for three weeks, prevents the disease of angina, catarrh of the upper respiratory tract. Dibazol stimulates the formation of interferon in cells, therefore, it is effective in some viral infections.

2.5 Preparations of different groups

thymosin. The main effect is the induction of maturation of T-lymphocytes. Data on the effect of thymosin on humoral immunity are contradictory. There is an opinion that by enhancing the manifestation of immune reactions, thymosin reduces the formation of autoantibodies. The effect of thymosin on cellular immune responses determined the scope of its clinical application: primary immunodeficiency states, tumors, autoimmune disorders, and viral infections.

vitamins. Vitamins, being coenzymes or part of them, due to their role in metabolic processes, have a very significant impact on the functions of various organs and systems of the body, including the immune system. The extremely wide use of vitamins, often in doses that are significantly higher than physiological, makes understandable the interest in their effect on the immune system.

a) vitamin C.

According to numerous data, vitamin C deficiency leads to a clear violation of the T-system of immunity, while the humoral immunity system is more resistant to C-vitamin deficiency. In addition to the dose, the nature of the combination of vitamin C with other drugs, for example, with B vitamins, is of great importance. Stimulation of phagocytosis is associated with its direct effect on phagocytes and depends on the dose of the drug. It is believed that vitamin C increases the sensitivity of bacteria to lysozyme. However, after prolonged therapy with large doses of vitamin C, a sharp hypovitaminosis of vitamin C may develop after stopping its intake.

b) Thiamine (B1).

With hypovitaminosis B1, there is a decrease in immunogenesis in relation to corpuscular antigens, a decrease in resistance to certain infections. The effect on phagocytosis occurs by interfering with the carbohydrate-phosphorus metabolism of phagocytes.

c) Cyanocobalamin (B12).

Obviously, the effectiveness of vitamin B12 in normal doses with extremely disturbed hematopoietic and immunological functions (violation of B-cell differentiation, a decrease in the number of plasma cells, antibodies, leukopenia, megaloblastic anemia, recurrent infection). But there is a stimulating effect of vitamin B12 on tumor growth (unlike B1, B2, B6). One of the main immunomodulating effects of vitamin B12 is the effect on the metabolism of nucleic acids and proteins.

Recently synthesized coenzyme drug B12 - cobamamide, which is non-toxic and has anabolic properties and, unlike vitamin B12, normalizes impaired lipid metabolism in patients with atherosclerosis.

General toning funds: preparations of magnolia vine, eleutherococcus, ginseng, radiola rosea.

Enzymatic drugs: lysozyme.

Antibiotics: with antigen-specific inhibition of phagocytosis.

Serpentine poison: medicinal preparations containing ophiditoxin (vipratoxin, viperalgin, epilarktin) increase the activity of complement and lysozyme, increase macrophage and neutrophilic phagocytosis.

trace elements.

3. Principles of differentiated immunocorrection

It is known that any disease is accompanied by the development of immunodeficiency states (IDS). There are methods for assessing the immune status that allow you to detect the affected parts of the immune system.

In most cases, nonspecific immunocorrection occurs. But keep in mind that many immunomodulators also cause non-immune effects. You might think that immunocorrection has no prospects. But it's not. You just need to approach this problem from two positions: 1.- in the body there are general universal reactions that reflect pathology. 2.- there are subtleties in the pathogenesis of many, for example, bacterial toxins that contribute to the mechanism of immune disorders.

From this we can conclude that the differentiated appointment of immunomodulators is relevant.

A significant disadvantage in the diagnosis of IDS is the lack of a clear gradation, so immunomodulators are often prescribed without taking into account the degree of immune disorders and the activity of the drug. There are three degrees of IDS:

1 degree - a decrease in the number of T cells by 1-33%

Grade 2 - a decrease in the number of T cells by 34-66%

3 degree - a decrease in the number of T cells by 67-100%

Immunological graphical analysis is used to determine the IDS. For example, with pyelonephritis, rheumatism, chronic pneumonia, the third degree of IDS is detected; in chronic bronchitis - the second; with peptic ulcer of the stomach and duodenum - the first.

The notion that most traditional medicines have no effect on the immune system seems to be erroneous and outdated. As a rule, they either stimulate or suppress the immune response. Sometimes a combination of traditional medicines, taking into account their immunotropism, can eliminate immunological disorders in patients. This is very important, because if the drug has an immunosuppressive property, which is unfavorable; the immunostimulatory property is also unfavorable, since it can contribute to the development of autoimmune and allergic conditions. With a combination of drugs, it is possible to enhance the immunosuppressive and immunostimulating effects. For example, the combination of antihistamines and antibacterial agents (penicillin and suprastin) contributes to the development of the suppressive qualities of both drugs.

It is very important to know the main targets of immunomodulators, indications for their use. Despite the certainty of action, tinosine, sodium nucleinate, LPS, levamisole activate all the main parts of the immune system, that is, they can be taken in any form of secondary IDS with deficiencies in T- and B-cell systems, the phagocytic system, and their combinations.

But drugs such as catergen, zixorin have a pronounced selectivity of action. The selectivity of the action of immunomodulators depends on the initial state of the immune status. That is, the effect of immunocorrection depends not only on the pharmacological properties of the drug, but also on the initial nature of immune disorders in patients. The drugs listed above are effective in violation of any part of the immune system, provided they are suppressed.

The duration of action of immunomodulators depends on their properties, mechanism of action, immunological parameters of the patient, the nature of the pathological process. Thanks to experimental studies, it has been established that repeated courses of modulation not only do not form the process of addiction or overdose, but increase the severity of the effect of the action.

Immune disorders rarely affect all parts of the immune system, more often they are isolated. Immunomodulators affect only altered systems.

A relationship has been established between immunomodulators and the genetic system of the body. In most cases, the maximum effectiveness of immunomodulators in patients with the second blood group in dysentery, with purulent infections of soft tissues - with the third blood group.

Indications for the use of monoimmunocorrective therapy are:

a) IDS 1-2 degree;

b) aggravated protracted clinical course of the disease;

c) severe concomitant pathology: allergic reactions, autoimmune reaction, malnutrition, obesity, malignant neoplasms. Elderly age.

d) atypical temperature reactions.

First, small immunocorrectors (methacin, vitamin C) are prescribed, if there is no effect, then more active drugs are used.

Combined immunocorrective therapy is the sequential or simultaneous use of several immunomodulators with different mechanisms of action. Indications:

1- chronic course of the main pathological process (more than three months), frequent relapses, concomitant complications, secondary diseases.

2- intoxication syndrome, metabolic disorders, protein loss (by the kidneys), helminthic invasion.

3- unsuccessful immunocorrective therapy within one month.

4- increase in the degree of IDS, combined damage to T- and B-links, T-, B- and macrophage links, multidirectional disorders (stimulation of some processes and inhibition of others).

It is necessary to highlight the concept of preliminary immunocorrection. Preliminary immunocorrection is a preliminary elimination of immune pathology to improve basic therapy; used for preventive purposes.

4. Mainprinciplesapplicationsimmunomodulators

1 . Mandatory assessment of the nature of immune disorders in patients.

2 . They are not used independently, but complement the traditional etiotropic therapy.

3 . Influence on the dependence of changes in immune parameters from age, biorhythms of the patient and other reasons.

4 . The need to determine the severity of immune disorders.

5 . Immunotropic effects of traditional medicinal substances.

6 . Attention to the targets of action of immunomodulators.

7 . Accounting for adverse reactions.

8 . The profile of the action of modulators is preserved in various diseases, but only in the presence of the same type of immune disorders.

9 . The severity of the correction effect in the acute period is higher than in the remission stage.

10 . The duration of the elimination of immune disorders depends on the properties of the drugs and the nature of the disease and ranges from 30 days to 1 year.

11 . With repeated use of immunomodulators, the spectrum of their action is preserved, the effectiveness increases.

12 . Immunomodulators do not affect unchanged immune parameters.

13 . The drug fully realizes its effects only in the optimal dose.

14 . A doctor's supervision is necessary to take into account the effectiveness of the immunomodulator.

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For citation: Dronov I.A. Immunostimulating therapy for recurrent respiratory infections in children: an evidence base for efficacy and safety // RMJ. 2015. №3. S. 162

Acute respiratory infections (ARI) account for at least half of all acute diseases in children, during the period of a seasonal increase in the incidence (mid-autumn to late spring) - up to 90%. The highest incidence is observed at preschool age - on average, children suffer from ARI 3-4 rubles / year, and 30-40% of them, the number of diseases is more than 6-8 cases per year.

The high incidence of ARI in children is associated with epidemic causes and transient abnormalities in the immune system due to its immaturity, such as:

• quantitative and functional deficiency of T-lymphocytes;
• deficiency in the formation of cytokines;
• deficiency of immunoglobulins (Ig) classes, A, M and G;
• deficiency of granulocytic and monocytic-macrophage chemotaxis, etc.

These changes increase the risk of ARI and at the same time often occur as a result of it. Thus, a vicious circle can form, causing a series of relapses of ARI.

The main causative agents of ARI are viruses (more than 200 serotypes of various species), less often - various bacteria, including atypical ones, and in some rare cases - fungi. The possibilities of etiological therapy and prevention in ARI are limited: specific immunoprophylaxis is used only for influenza, and therapy has been developed for bacterial infections (the proportion of which is small) and only certain viral infections: influenza, respiratory syncytial infection, and some others. In this regard, there is a need for widespread use of pathogenetic therapeutic and prophylactic agents, primarily drugs that increase the immune response against ARI pathogens.

In the Russian Federation, according to the State Register of Medicines as of February 15, 2015, more than 100 immunostimulants and more than 50 immunomodulators are registered, most of which are positioned as drugs for the prevention and treatment of ARI. In addition, these indications are noted in a number of immunobiological preparations. However, only for some of these drugs in the scientific literature is there a sufficient number of evidence-based clinical studies that confirm their high efficacy and safety, and therefore make it possible to recommend them for widespread use in pediatric practice.

Of greatest interest is the Cochrane systematic review on the use of immunostimulants for the prevention of respiratory tract infections in children. The review authors analyzed more than 700 publications from 1966 to 2011, from which 61 placebo-controlled clinical trials were selected. These studies determined the efficacy and safety of various immunostimulants: 40 - bacterial preparations (lysates, ribosomes, antigens), 11 - synthetic preparations, 5 - thymus extract, 4 - herbal preparations and 1 - interferon. The meta-analysis included only 35 studies (including more than 4 thousand children) that contained the necessary data on the frequency of ARI. The results showed that, on average, the use of immunostimulants reduces the incidence of ARI by about 36%.

The largest number of placebo-controlled clinical trials was devoted to the study of the bacterial preparation D53 (ribomunil) - 18 (of which 11 were included in the meta-analysis), but there were no category A studies (well-designed studies conducted on a sufficient number of patients), in addition, all studies continued for 6 months. or less. Bacterial preparations OM-85 BV (Broncho-Vaxom) were studied in 12 placebo-controlled clinical trials (of which 9 were included in the meta-analysis). At the same time, there were 4 studies of category A, and the duration of all studies was 6 months. or more.

Overall, this systematic review demonstrated a significant efficacy of immunostimulants. First of all, this applies to the 2 above bacterial preparations compared with placebo. It should be noted that the frequency of adverse events from the gastrointestinal tract and skin when using immunostimulants did not differ significantly from that when using placebo.

The literature presents a number of meta-analyses on the use of immunostimulants in recurrent ARI in children. C. de la Torre González et al. the effectiveness of immunostimulants used in pediatric practice in Mexico was analyzed. It has been established that only 5 drugs have randomized, double-blind, placebo-controlled clinical trials: OM-85 BV, D53, LW50020 (luivak), RU41740 and pidotimod. For 4 drugs, data were presented to assess their long-term effectiveness. Table 1 shows the reduction in the frequency of ARI with the use of various immunostimulants. As can be seen from Table 1, the greatest effect, according to the meta-analysis, was observed when using the drug OM-85 BV (Broncho-Vaxom). The authors noted that the results of evidence-based clinical studies conducted in Mexico showed an even greater effect when using OM-85 BV - a 46.85% reduction in the incidence of ARI compared with placebo.

These studies indicate the high efficiency of bacterial immunostimulants OM-85 BV (Broncho-Vaxom). This preparation is a standardized lyophilized lysate of 8 bacteria (4 gram-positive and 4 gram-negative): Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Klebsiella ozaenae. Studies show that bacterial lysates are able to have a significant regulatory effect on the function of the immune system. In modern conditions, children lack microbial stimulation of the immune system, which is due to the high level of hygiene, the relative rarity of bacterial infections, and the frequent use of antibiotics. This leads to a decrease in the Th-1 immune response (associated with a subpopulation of type 1 T-helpers) and a decrease in the production of a number of cytokines that provide activation of the anti-infective immune response: γ-interferons, interleukins-1, -2, etc. Suppression of the production of these cytokines may also be due to the very frequent use of antipyretics in infectious diseases. At the same time, there is an increase in the strength of the Th-2 immune response (associated with a subpopulation of type 2 T-helpers), which, in particular, contributes to the overproduction of IgE antibodies and the development of allergic reactions. The use of bacterial lysates leads to stimulation of the Th-1 immune response and a simultaneous decrease in the Th-2 immune response, which is manifested by an increase in the level of anti-infective protection and a decrease in the production of IgE. As a result, not only the frequency of infectious diseases (primarily respiratory) decreases, but also the likelihood of developing allergic diseases. The use of bacterial lysates leads to an increase in the production of antibodies of the IgA class (including secretory ones), Nk cells (lymphocytes are natural killers).

More than 40 randomized clinical trials of the immunostimulant OM-85 BV (Broncho-Vaxom) are presented in the scientific literature, of which approximately half included pediatric patients. Several meta-analyses and systematic reviews are also presented. One meta-analysis analyzed the efficacy of OM-85 BV in children, assessing the effect of the drug on the frequency and duration of ARIs, as well as on the need for antibiotic therapy. The authors analyzed 13 randomized clinical trials, however, due to heterogeneity, only 2 or 3 studies were included in the meta-analyses for each item assessed. It has been shown that with the use of OM-85 BV there is a tendency to reduce the frequency and duration of ARI, as well as the need for the use of antibiotics. It should be noted that this meta-analysis was criticized due to the fact that it did not include individual evidence-based studies, as well as due to the choice of analysis methodology by the authors.

A more recent meta-analysis also assessed the efficacy of OM-85 BV in children (aged 1 to 12 years), namely the proportion of patients who had 1 episode of ARI, the proportion of patients who had 3 or more episodes of ARI, and the number of episodes of ARI in 6 months Eight evidence-based clinical studies (about 800 patients) were analyzed. The proportion of patients who had for 6 months. at least 1 episode of ARI was 16.2% lower in the main group than in the placebo group (72.7 and 88.9%, respectively, p<0,001). Доля пациентов, имевших за 6 мес. 3 и более эпизодов ОРИ, была на 26,2% ниже в основной группе, чем в группе плацебо (32 и 58,2% соответственно, p<0,00001). Среднее число ОРИ за 6 мес. в основной группе оставило 2,09±1,79, а в группе плацебо - 3,24±2,40 (p<0,001). Также была проанализирована безопасность использования ОМ-85 BV: в основной группе нежелательные эффекты наблюдались у 17,7%, в группе плацебо - у 18,2% детей, частота отмены препарата из-за нежелательных эффектов составила 1,3 и 0,7% соответственно. В целом данный метаанализ свидетельствует о высокой эффективности и безопасности применения иммуностимулятора ОМ-85 BV у детей с рецидивирующими ОРИ .

In a number of clinical studies, not only the preventive effect of the drug OM-85 BV was evaluated. aspect of reducing the frequency of ARI relapses, but also other parameters.

A randomized, double-blind, placebo-controlled study included 75 children aged 1 to 6 years with a history of episodes of bronchial obstruction (wheezing) provoked by ARI in anamnesis. Within 1 year after the course of treatment with OM-85 BV, patients in the main group had an average of 2.44 fewer cases of ARI (5.31±1.79 and 7.75±2.68, respectively, p<0,001). У пациентов в основной группе было отмечено в среднем на 2,18 эпизода бронхообструкции меньше, чем у пациентов в группе плацебо (3,57±1,61 и 5,75±2,71 соответственно, разница 37,9%, р<0,001). При этом средняя продолжительность эпизода бронхообструкции была на 2,09 дня короче в основной группе, получавшей ОМ-85 BV, чем в группе плацебо (5,57±2,10 и 7,66±2,14 соответственно, р<0,001). Таким образом, данное исследование показало, что назначение ОМ-85 BV у детей дошкольного возраста не только достоверно уменьшает частоту ОРИ, но также снижает частоту и сокращает длительность провоцируемых ими эпизодов бронхообструкции .

A number of studies have simultaneously evaluated the therapeutic and prophylactic effects of OM-85 BV in children. So, in a double-blind, randomized, placebo-controlled study, the effectiveness of an immunostimulant was evaluated in 56 children aged 1.5 to 9 years with sinusitis. Patients in both groups received amoxicillin / clavulanic acid, and in the main group - an additional course of OM-85 BV. In the group of patients treated with an immunostimulant, a positive effect was noted significantly faster than in the group treated with placebo (5.56±4.98 and 10±8.49 days, respectively, p<0,05) и выздоровление (15,38±8,91 и 20,28±7,17 дня соответственно, р<0,05). Наблюдение за пациентами в течение 6 мес. показало, что в основной группе достоверно реже наблюдались рецидивы ОРИ (1,556±0,305 и 2,222±0,432 случая соответственно, р<0,05), реже требовалось применение антибактериальной терапии (1,118±0,308 и 1,722±3,78 назначения соответственно, р<0,05) .

Interesting data were obtained in a retrospective analysis of case histories of 131 children aged 1 to 15 years with recurrent acute tonsillitis treated with OM-85 BV. 51.2% of patients had a complete clinical response (more than 50% reduction in recurrence rate), 24.4% had a partial clinical response (less than 50% reduction in recurrence rate), and another 24.4% responded to therapy was not received (the frequency of relapses did not decrease). None of the children with a complete clinical response required tonsillectomy; 34.4% of children with a partial clinical response and 84.3% of children without a response to therapy required a tonsillectomy. In general, this study indicates that the use of the OM-85 BV immunostimulant in children with recurrent acute tonsillitis in most cases achieves a clinical effect and avoids tonsillectomy.

Of great interest is the French pharmacoeconomic study, which determined the cost-effectiveness of using the drug OM-85 BV for the prevention of recurrent infections of the upper respiratory tract in children. It has been shown that the use of this immunostimulant leads to a significant reduction in direct costs for the treatment of ARI.

The accumulated scientific data on the clinical use of the immunostimulant OM-85 BV made it possible to include this drug in international consensus recommendations. OM-85 BV is the only immunostimulant included in the European Memorandum on Rhinosinusitis and Nasal Polyps 2012 (under the treatment of chronic rhinosinusitis).

To date, the scientific literature contains a large number of publications with the results of clinical studies confirming the high efficacy and safety of the use of the OM-85 BV immunostimulant in children. The original drug is presented on the Russian market in the form of capsules in 2 versions: Broncho-Vaxom ® adult (contains 7 mg of standardized lyophilized OM-85 bacteria lysate and is intended for use in children over 12 years of age and adults) and Broncho-Vaxom ® for children ( contains 3.5 mg of standardized lyophilized OM-85 bacteria lysate and is intended for use in children from 6 months to 12 years of age). The drug is recommended for the prevention of recurrent respiratory tract infections and exacerbations of chronic bronchitis, as well as acute respiratory tract infections as part of complex therapy. For therapeutic purposes, it is necessary to take the drug daily (1 capsule in the morning before meals) for at least 10 days, for prophylactic purposes - 3 courses of treatment (1 capsule in the morning before meals) for 10 days with breaks between courses of 20 days.

Literature

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The essence of this type of pathogenetic therapy is the use of drugs whose action is aimed at activating the functions of the immune system. Substances that normalize its function are called immunomodulators (modulatio - state change) or immunocorrectors (corectio - correction). The use of immunomodulators has various goals: restoration of the functions of the immune system; prevention of various diseases in immunodeficiency states (IDS); increasing the body's immune defense in diseases accompanied by the development of immunosuppression; improving the effectiveness of vaccines and medicines.

Evidence-based principles for the use of immunomodulators are as follows: a) the choice of immunomodulators should be based on their ability to correct those parts of the immune system, the violation of which occurs in this pathology; b) the timing of the introduction of immunomodulators should provide maximum protection during the most dangerous periods of animal life; c) immunomodulators must be used in combination with other treatments; d) it is necessary to use drugs against the background of improving the conditions of keeping and feeding animals; e) it is necessary to use immunocorrectors under the control of indicators that provide objective information about the state of the immune system.

The mechanism of action of many immunomodulators is still far from being understood. The stimulating effect of immunotropic drugs is based on the effect of non-specific protection, which is carried out through phagocytosis, the synthesis of complement, interferon and lysozyme, stimulation of the activity of macrophages, T- and B-lymphocytes, and the synthesis of immunoglobulins. The mechanism of action of immunomodulators largely depends on the type of drug, its dose, the nature of the pathology, the immune background on which the drug is used.

In practice, the following immunomodulators are widely used: vitamins, micronutrients(І, Se, Co, Zn, Fe), immunoglobulins, adaptogens, probiotics, cytomedins, including thymus preparations, interferons, interleukins, bone marrow preparations, avian bursa of Fabricius, adjuvants.

Adaptogens there are vegetable (tinctures of ginseng, eleutherococcus, Chinese magnolia vine, extracts of aloe leaves, gumizol, sodium humate) and animal (pancreatin, tissue preparations, apilac, etc.) origin. Now drugs of known chemical structure have been proposed: quaterin, fumaric acid, sodium succinate, chlorpromazine, phenazepam, dibazol, sodium bromide.

At the turn of the 80s, the immunomodulatory effect of derivatives was established. imidazole - levamisole and camisole, which stimulate the maturation of T-suppressors and T-effectors, phagocytosis, the synthesis of immunoglobulins. The drugs are used in secondary immunodeficiency conditions, in the treatment of acute respiratory diseases of newborns, hepatitis, acute infectious diseases, purulent arthritis and other diseases.

The most promising immunomodulators are cytomedins, which are metabolic products of the body. They stimulate the immune, endocrine and nervous systems. In recent years, thymus preparations (thymosin, thymalin, T-activin, thymogen, thymoptin, vilozen, thymomulin, thymotropin), interferon, and interleukins have been widely used.

Thymus preparations are used in the complex therapy of respiratory and gastrointestinal diseases of young animals, in acute intoxications, infectious diseases, post-surgical complications, to enhance the body's immune response to the introduction of vaccines.

Interleukins- These are mediators of macrophage and leukocyte origin, which are factors that activate immunocompetent cells - lymphocytes. The high efficiency of the use of interleukins in the complex of therapeutic and preventive measures for pneumonia in pigs, vesicular stomatitis in cattle, and purulent-inflammatory processes was revealed.

Bone marrow preparations are considered promising myelopeptide and B-activin. They regulate various biological processes, including immunity, stimulate the synthesis of antibodies, and regulate the reactions of T-cell immunity. Effective is the joint use of T- and B-activin in infectious rhinotracheitis, bronchopneumonia in calves, gastroenteritis. Myelopeptides of immunostimulatory action are also obtained from the Fabricius bag - bursilin and bursin.

Among immunocorrectors, lipopolysaccharides of gram-negative bacteria are well known - pyrogenal and prodigiosan. Pyrogenal stimulates the functional activity of leukocytes, mononuclear phagocytes, the synthesis of antibodies. Prodigiosan stimulates the production by macrophages of a factor that activates T-lymphocytes, enhances the synthesis of interferon, antibodies and other humoral immunity factors (complement, properdin, lysozyme). With intramuscular administration of prodigiosan, its immunostimulating effect reaches a maximum in a day and remains at a constant level for 7-10 days. The drug was successfully used to treat calves with bronchopneumonia (Karput I. M., 1989). An even more pronounced stimulating effect is exerted by the microbial polysaccharide "Salmopul", obtained from bird salmonella. It is used to prevent age-related and acquired immune deficiencies, gastrointestinal and other diseases that occur against the background of immune deficiency (Karput I.M., Babina M.P., Kovzov V.V., Proshchenko V.M.).

Obtained from fodder yeast zymosan and sodium nucleinate, which enhance the activity of macrophages, neutrophils, T-lymphocytes, stimulate the differentiation of lymphocytes into antibody-producing cells. Sodium nucleinate, effective in the complex therapy of calves with bronchopneumonia, is used to prevent gastrointestinal diseases of calves in the neonatal period, stimulate the immune response during vaccination of calves and piglets against salmonellosis, piglets against Aujeszky's disease and leptospirosis.

Immunocorrective therapy - These are therapeutic measures aimed at the regulation and normalization of immune responses. For this purpose, various kinds of immunotropic drugs and physical effects are used (UV irradiation of blood, laser therapy, hemosorption, plasmapheresis, lymphocytopheresis). The immunomodulatory effect during this type of therapy largely depends on the initial immune status of the patient, the treatment regimen, and in the case of the use of immunotropic drugs, also on the route of their administration and pharmacokinetics.

Immunostimulating therapy represents a type of activation of the immune system with the help of specialized means, as well as with the help of active or passive immunization. In practice, both specific and non-specific methods of immunostimulation are used with the same frequency. The method of immunostimulation is determined by the nature of the disease and the type of disorders in the immune system. The use of immunostimulating agents in medicine is considered appropriate in chronic idiopathic diseases, recurrent bacterial, fungal and viral infections of the respiratory tract, paranasal sinuses, digestive tract, excretory system, skin, soft tissues, in the treatment of surgical pyoinflammatory diseases, purulent wounds, burns, frostbite, postoperative purulent-septic complications.

Immunosuppressive therapy - the type of influences aimed at suppressing immune responses. Currently, immunosuppression is achieved with the help of non-specific medical and physical means. It is used in the treatment of autoimmune and lymphoproliferative diseases, as well as in organ and tissue transplantation.

Replacement immunotherapy - This is a therapy with biological products to replace defects in any part of the immune system. For this purpose, immunoglobulin preparations, immune sera, leukocyte suspension, hematopoietic tissue are used. An example of substitution immunotherapy is the intravenous administration of immunoglobulins for hereditary and acquired hypo- and agammaglobulinemia. Immune sera (anti-staphylococcal, etc.) are used in the treatment of sluggish infections and purulent-septic complications. A suspension of leukocytes is used for Chediak-Higashi syndrome (a congenital defect of phagocytosis), hematopoietic tissue transfusion - for hypoplastic and aplastic conditions of the bone marrow, accompanied by immunodeficiency states.

Adoptive immunotherapy - activation of the body's immune reactivity by transferring non-specifically or specifically activated immunocompetent cells or cells from immunized donors. Nonspecific activation of immune cells is achieved by culturing them in the presence of mitogens and interleukins (in particular, IL-2), specific - in the presence of tissue antigens (tumor) or microbial antigens. This type of therapy is used to increase antitumor and anti-infective immunity.

Immunoadaptation - a set of measures to optimize the body's immune responses when changing geoclimatic, environmental, light conditions for human habitation. Immunoadaptation is addressed to persons who are usually classified as practically healthy, but whose life and work are associated with constant psycho-emotional stress and tension of compensatory-adaptive mechanisms. Residents of the North, Siberia, the Far East, high mountains need immunoadaptation in the first months of living in a new region and upon returning to their permanent place of residence, people working underground and at night, on a rotational basis (including duty personnel of hospitals and stations ambulance), residents and workers of ecologically unfavorable regions.

Immunorehabilitation - a system of therapeutic and hygienic measures aimed at restoring the immune system. It is indicated for persons who have undergone serious illnesses and complex surgical interventions, as well as for persons after acute and chronic stressful effects, large prolonged physical exertion (athletes, sailors after long trips, pilots, etc.).

Indications for the appointment of a particular type of immunotherapy is the nature of the disease, insufficient or pathological functioning of the immune system. Immunotherapy is indicated for all patients with immunodeficiency conditions, as well as for patients whose development of diseases includes autoimmune and allergic reactions.

The choice of means and methods of immunotherapy, schemes for its implementation should be based primarily on the analysis of the work of the immune system, with a mandatory analysis of the functioning of the T-, B- and macrophage link, the degree of involvement of immune reactions in the pathological process, and also taking into account the effect of immunotropic agents on a specific link or stage
development of the immune response, properties and activity of individual
populations of immunocompetent cells. When prescribing an immunotropic drug, the doctor in each case determines its dose, amount and frequency of administration.

Immunotherapy should be carried out against the background of good nutrition, taking vitamin preparations, which include micro and macro elements. An important point in the conduct of immunotherapy is the laboratory control over its implementation. Staged immunograms make it possible to determine the effectiveness of the therapy, to make timely corrections to the chosen treatment regimen, and to avoid unwanted complications and negative reactions. It should be emphasized that the unreasonable use of immunotherapy methods, the wrong choice of the means of its implementation, the dose of the drug and the course of treatment can lead to the prolongation of the disease and its chronicity.