RU2296999C2 - Method of detecting the criteria for carrying out adequate imunotherapy of purulent-septic diseases - Google Patents

Abstract

FIELD: medicine, immunology.

SUBSTANCE: it is necessary to detect IgG or CD3-lymphocytes level both before and after applying immunomodulator at the background of conventional therapy. One should select the group of patients with increased and another group with decreased value of immunological parameter at the background of immunotherapy. If the best clinical efficiency has been achieved in the group of increased initial immunological value it is possible to determine the possible maximal value of immunological parameter in the group before the onset of immunotherapy; at establishing the initial immunological parameter being below against the obtained maximal value of this parameter in the group application of the present immunomodulator should be considered the most useful. If the best clinical efficiency has been achieved in the group of decreased initial immunological parameter one should determine the possible minimal value of immunological parameter in this group before the onset of immunotherapy; at detecting initial immunological parameter being above the established maximal value of this parameter in this group application of the present immunomodulator should be considered the most rational.

EFFECT: higher accuracy and efficiency of detection.

4 ex

Description

The invention relates to medicine, namely to immunology, and allows you to determine the criteria for the use of immunomodulators in the treatment of purulent-septic diseases, as well as to predict the direction of change of immunological parameters during immunotherapy and select the optimal immunomodulator.

The use of therapeutic and prophylactic drugs with immunomodulatory properties is becoming increasingly common in the activities of doctors of various specialties. At the same time, despite the constant increase in the number of immunotropic drugs, the problem of substantiating the appointment and development of criteria for the effective use of immunotherapy agents that are not only related to newly developed, but also considered in the form of traditional [Azolov V.V. The Russian burn service at the present stage - problems and possibilities of their solution / V.V. Azolov, V. A. Zhegalov, S. P. Peretyagin // Mat. VII All-Russian. scientific - prakt. conf. on the problem of thermal damage. - Chelyabinsk, 1999. - C.3-6; Immunodeficiency States / Ed. prof. Smirnova V.S. and prof. Freidlin I.S. - St. Petersburg: "Tome", 2000. - 568 p .; Immunodiagnosis and immunocorrection in clinical practice / Ed. I.D. Stolyarova. - SPb .: SOTIS, 1999. - 176 p .; Immunotherapy for allergies and microbes / N.D. Beklemishev, V.S. Moshkevich, G.S. Sukhodoeva, V.P. Tsoi, L.P. Tsarevsky, I.L. Kasatkina, N.A. Aspetova. - Alma-Ata: Science, 1980 .-- 304 p .; Kadagidze 3.G. Current approaches to tumor immunotherapy // Inter J. Immunorehabilitation. - 1998. - No. 10. - S. 54-65; Medvedev Yu.A. Fundamentals of immune and immuno-directed methods of therapy and prevention / Yu.A. Medvedev, M.M.Alsynbaev. - Ufa: RIO GUP "Immunopreparat". - 2000. - 82 p .; Hadden J. Immunostimulants // Iimmmol. Today. - 1993 .-- Vol.14. - P.275-280].

The role of the immune system and nonspecific resistance of the body in the development of purulent inflammatory processes in surgery is indicated by many authors [Beklemishev ND Immunopathology and immunoregulation // M. - Medicine. - 1986; Mayansky A.N., Mayansky D.N. Essays on neutrophil and macrophage // Novosibirsk. - The science. - 1983. - 254 p .; Struchkov V.I., Nedvetskaya L.M., Prozorovskaya K.N. Immunology in the prevention and treatment of purulent surgical diseases // M. - Medicine. - 1978. - S. 269]. Immunity disorders in patients with purulent-inflammatory complications affects both the populations and subpopulations of T and B lymphocytes and the cells of the phagocytic system [Drobkov L.Z., Nazarov N.V. Features of early immunological changes in patients with peritonitis // Clinical surgery. - 1985. - No. 1. - S.17-18; Eustache M. L., Petit J., Gelbert D. Et al. Immunoregulatory cells in patients with acute peritonitis // Pres med. - 1984. - Vol.13. - No. 46. - P.2813]. This leads to the development of secondary immunodeficiencies, the timely detection and correction of which is one of the conditions for successful treatment [Lopukhin Yu.M., Petrov RV, Kovalchuk LV, Arion V.Ya. Modern ideas about human immunodeficiencies: diagnostics and correction methods // Immunodeficiency states and correction methods. - M. - 1981. - S.6-16; Lopukhin Yu.M., Petrov R.V., Kovalchuk L.V., Cheredeyev A.I., Molodenkov M.I. Actual tasks of clinical immunology and immunocorrection - correction of immune disorders in the clinic and experiment // M. - 1985. - P.6-12].

Currently, in the treatment of infectious pathology of the surgical plan, an approach is used that involves a combination of surgical debridement of the foci of infection with the implementation of the immuno-therapeutic plan, many times increasing the chances of achieving radical treatment results or longer remission [Drobkov L.Z., Nazarov N.V. Features of early immunological changes in patients with peritonitis // Clinical surgery. - 1985. - No. 1. - S.17-18; Chereshnev V.A., Kevorkov N.N., Bakhmetyev B.A., Chereshneva M.V. The principles of complex immunorehabilitation of patients with secondary immunodeficiency // Imtemational Jounal on Immunorehabilitation. - 1997. - No. 4. - C.5; Eustache M. L., Petit J., Gelbert D. Et al. Immunoregulatory cells in patients with acute peritonitis // Pres med. - 1984. - Vol.13. - No. 46. - P.2813].

Despite numerous studies in the field of prevention and treatment of purulent-septic pathology caused by opportunistic bacteria [Belotsky S.M. Immunology of surgical infections (scientific review). - M., 1980. - 104 s .; Bone R. Sepsis and septic shock / Course of lectures: Actual problems of anesthesiology and intensive care. IX European Congress of Anesthesiologists, October 2-7, 1994 - Arkhangelsk-Tramse, 1995. - P.125-139; Bulgakova A.I. Improving the local therapy of chronic generalized periodontitis: Abstract. dis. Cand. honey. Sciences, - M., 1999. - 22 p .; Struchkov V.I. Immunology in the prevention and treatment of purulent surgical diseases / V.I. Struchkov, L.M. Nedvetskaya, K.N. Prozorovskaya. - M .: Medicine, 1978. - P.269; Balk R. A. The septic syndrome: Definition and clinicalimplication / R. A. Balk, R. C. Bone // Crit. Care Clin. - 1989. - Vol.5 - P.1-8; Bone R.C. Gram-negative sepsis: a dilemma of modem medicine / Clin. Microb. Rev.- 1993. - Vol.6, No. 1. - P.57-68; Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis / R.C. Bone, R.A. Balk, F.B. Kerra et al. // Chest. - 1992. - V.101, No. 6. - P.1644-1655], as well as the existence of a variety of tools and methods used in this case, the issues of immunotherapy and immunoprophylaxis of purulent-septic diseases need further development [Immunodiagnosis and immunocorrection in clinical practice / Ed. I.D. Stolyarova. - SPb .: SOTIS, 1999. -176 p .; Kokoulina Zh.N. Prevention and intensive care of secondary immunodeficiency and purulent-septic complications in burn patients: Abstract. dis .... cand. honey. sciences. - Novosibirsk, 1998 .-- 22 p .; Pinegin B.V. Immunodiagnosis and immunotherapy of surgical infections / B.V. Pinegin, T.M. Andronova, T.I. Yudina // Int. J. Immunorehabilitation. - 1998. - No. 10. - S.86-99; Khaitov R.M. Immunodiagnostics and immunotherapy of immune system disorders / R.M.Khaitov, B.V. Pinegin // Practicing physician. - 1997. - No. 9. - S.5-13].

Today, there are several points of view on the tactics of using immunomodulators. According to some authors, their appointment should always be based on the results of clinical and immunological examinations, while the clinical picture serves as the main criterion for the appointment of immunomodulators. In this regard, the latter should be used in complex therapy of patients of the following groups [R.M. Khaitov, B.V. Pinegin. Secondary immunodeficiencies: clinic, diagnosis, treatment. J. Immunology, 1999, No. 1. Moscow .: Medicine. S.14-17; R.M.Khaitov, B.V. Pinegin. Modern immunomodulators: the basic principles of their application. J. Immunology, 2000, No. 5. Moscow .: Medicine. C.4-7]:

- persons with clinical signs of impaired immunity in combination with specific changes in its parameters identified using immunological methods;

- Persons with only clinical signs of impaired immunity without changing its parameters.

Thus, in the presence of a chronic infectious and inflammatory process, the patient can be prescribed immunomodulating drugs even if the immunodiagnostic study did not reveal significant deviations in the immune status.

Other authors recommend not prescribing immunomodulating drugs without conducting an investigation of the immune status, so that instead of helping not to harm the patient [R.I. Sepiashvili. Classification and basic principles of the use of immunomodulating drugs in clinical practice. Allergology and immunology. Volume 3, No. 3, October 2002, S.325-331]. This method is taken as a prototype. With pronounced clinical signs of the disease, when no changes in the patient’s immune system are detected, it is recommended to conduct a dynamic monitoring of the patient’s immune status before prescribing immunotropic drugs.

When conducting immunotherapy, there is a tactic for the appointment of an immunomodulator taking into account the predominant effect on certain cells or links of the immune system [R.M. Khaitov, B.V. Secondary immunodeficiencies: clinic, diagnosis, treatment. J. Immunology, 1999, No. 1. Moscow .: Medicine. S.14-17].

The modern arsenal of immunotherapy tools allows for the directed restoration or correction of impaired immune defense mechanisms, but it requires clear immunodiagnostic criteria for the use of different immunotherapy agents in the complex of therapeutic measures even in patients with the same type of disease [Tupchiev KB Clinical and immunological parallels in osteomyelitis and immunocorrective therapy in the complex treatment of patients // Dis. Cand. honey. sciences. - Moscow. - 1987; Stepanenko R.N., Ryazanov N.K., Moldokulov O.A., Vlasenko R.Ya. Myelopid: immunocorrective activity in facial fractures and traumatic osteomyelitis // Immunology. - 1991. - No. 1. - S. 44-47; Zemskov A.M., Karaulov A.N., Zemskov V.M. Combined immunocorrection // M .: Science. - 1994. - 260 s .; Khaitov P.M., Pinegin B.V. Immunomodulators and some aspects of their clinical use // Clinical medicine. - 1996. - No. 8. - S.7-13; Pinegin B.V., Andronova T.M., Yudina T.I. Immunodiagnosis and immunotherapy of surgical infections. // International Journal on immunorehabilitation. - October - 1998. - N.10. - S.86-99].

However, there is still no differential characteristic of immunomodulators and clear instructions on which diseases it is better to prescribe this or that drug; indications and contraindications for these drugs have not been developed; it is not clear under what conditions they must be appointed, under which it is desirable, and under which it is strictly forbidden [R.I. Sepiashvili. Classification and basic principles of the use of immunomodulating drugs in clinical practice. Allergology and immunology. Volume 3, No. 3, October 2002, S.325-331].

The technical result is an improvement in the quality of treatment of patients due to adequate immunotherapy. The ranges of values of immunological indicators identified by this method for the effective use of immunomodulators can include not only lower values, but also the level of these indicators, which corresponds to both the normal range and the one above them. Thus, the immunological indications for the effective administration of immunomodulators are expanding. The criteria established by this method for the administration of various immunotropic drugs make it possible to carry out differential immunotherapy, prescribing the most appropriate immunomodulator for a particular patient.

The study used various immunotropic drugs (immunoglobulin for intravenous administration - immunovenin, human leukocyte interferon in suppositories, roncoleukin, ceruloplasmin) in the complex of treatment of 255 patients with purulent-inflammatory diseases (sepsis, chronic osteomyelitis, furunculosis, peritoneal abscess, abscess ), as a rule, immediately after surgical treatment based on clinical indications for use specified in the instructions for these drugs. In the hospital, patients underwent basic therapy in the form of surgical treatment of the focus of infection, antibacterial, detoxification and vitamin therapy, physiotherapy.

The following general clinical indicators of treatment effectiveness were evaluated: the duration of hospitalization of the patient in the hospital, the duration of the period of hyperthermia from the moment of initiation of immunotherapy; clinical outcomes of the disease (recovery, improvement, death).

The treatment process was controlled by general clinical laboratory [Medvedev VV, Volchek Yu.Z. Clinical laboratory diagnostics // Ed. prof. V.A. Yakovleva. - "Hippocrates", 1997. - 206 p.] And radiological research methods.

The state of the immune system was studied using a set of tests to assess the immune status of levels 1 and 2 in the dynamics of treatment with determination of the content of the main populations and subpopulations of lymphocytes. The data obtained were compared with the norm values adopted in the immunological laboratory of the RKB im. G.G. Kuvatova based on the results of a survey of 50 healthy donors. The study of the immune system was carried out according to generally accepted methods [Methodical recommendations, M., 1984; Laboratory research methods in the clinic (under the editorship of Menshikov VV), M., 1987].

Studies of the immune status were carried out before and after the completion of the course of immunotherapy. In the development of a methodology for assessing the state of the immune system of patients for the diagnosis of immunodeficiency states (IDS), we used data on changes in clinical and laboratory parameters for various typical pathological processes of an inflammatory nature, cited in the literature [Petrov R.V. Immunology // M .: Medicine. - 1987. - 311 p .; Zemskov A.M., Karaulov A.N., Zemskov V.M. Combined immunocorrection // M .: Science. -1994. - 260 s .; Khaitov P.M., Pinegin B.V., Istamov H.I. Ecological immunology // M .: VNIRO. - 1995. - 220 s .; Stephanie D.V., Veltishchev Yu.E. Immunology and immunopathology of childhood. II M.: Medicine. - 1996. - 384 p.].

Analyzing the clinical results and the dynamics of laboratory parameters obtained in the treatment of patients with purulent-septic diseases with the use of immunotherapy, it was noted that immunological parameters while taking different immunomodulators had different directions of change (in some cases, the values increased, in others - decreased). Even within the framework of one clinical group, where the same immunomodulator was used, the considered immunological index in some patients increased, in others it decreased.

This served as the basis for dividing all patients within each type of immunodeficiency into 2 groups: the first group included patients whose value of the considered immunological index increased during immunotherapy, the second group included patients whose value of the considered immunological index decreased during immunotherapy.

Subsequently, the set of initial values (obtained before the start of immunotherapy) of the immunological indicator for each clinical group was subjected to statistical analysis with the determination of the arithmetic mean and the limits of possible fluctuations of this indicator [Excel 2000 computer program using standard methods of variation statistics; The main methods of statistical research. Methodical instructions // St. Petersburg. - 1997. - 101 p.]. For this, the following calculations were performed:

1. Calculate the arithmetic mean for a given variation series:

,

,

where M is the arithmetic mean;

V is the value of the variation characteristic;

n is the total number of observations.

2. Calculate the standard deviation;

,

,

where δ is the standard deviation;

d - deviation of each option from the average;

p is the frequency of each option;

n is the total number of observations.

3. We calculate the average error of the arithmetic mean:

,

,

where m is the arithmetic mean error;

δ is the standard deviation;

n is the total number of observations.

4. Calculate the boundaries of the possible size of the phenomenon under study with a 95.5% confidence probability;

V _max = M + 2m,

where V _max - the possible maximum value of the indicator with a 95.5% confidence probability;

M - arithmetic mean;

m is the average error of the arithmetic mean.

V _min = M-2m,

where V _min is the possible minimum value of the indicator with a 95.5% confidence probability;

M - arithmetic mean;

m is the average error of the arithmetic mean.

Thus, the critical values of the fluctuation of the indicator (V _max and V _min ) were obtained in each group of patients.

At the same time, each clinical group within a certain type of IDS was compared by general clinical indicators: the length of hospitalization of the patient in the hospital, the duration of the period of hyperthermia from the moment of initiation of immunotherapy; clinical outcomes of the disease (recovery, improvement, death).

Thus, the clinical group with the best treatment results is determined and it becomes obvious - an increase or decrease in the initial value of the immunological indicator in the complex of therapy contributed to an improvement in the quality of treatment.

The proposed method for selecting the optimal immunomodulator is as follows. Before the appointment of immunotherapy determine the immune status of the patient. The tactics of choosing a drug for immunotherapy depends on in which clinical group the best treatment outcomes were obtained previously with this drug - against the background of an increase or decrease in the initial values of the immunological indicator. If, according to preliminary calculations, the best results are obtained against the background of increasing the initial values of this immunological indicator, then this immunomodulator is advisable to use the patient only if the value of the patient’s immunogram is less than V _max for this drug. If the patient’s immunogram indicator is higher than V _max for this drug, then the use of this immunomodulator against the background of complex therapy will contribute not to an increase, but rather a decrease in the initial value of the immunogram indicator, which will be accompanied by a deterioration in clinical indicators: increase in the duration of hospitalization, period of hyperthermia; worsening clinical outcomes of the disease.

If, according to preliminary calculations, the best results are obtained against the background of a decrease in the initial values of this immunological indicator, then this immunomodulator is advisable to use in a patient if the value of the patient’s immunogram is higher than V _min for this drug. If the patient’s immunogram indicator is lower than V _min for this drug, then the use of this immunomodulator against the background of complex therapy will not reduce, but rather increase the initial value of the immunogram indicator, which will be accompanied by a deterioration in clinical indicators: an increase in the duration of hospitalization and the period of hyperthermia; worsening clinical outcomes of the disease.

Using the proposed method, for the first time it became possible to determine the criteria for the use of almost any immunomodulators in the clinic of purulent-septic diseases.

This method for the first time defined clear criteria for use for immunotherapy in the clinic of purulent-septic diseases of such drugs as immunovenin, interferon, roncoleukin, ceruloplasmin.

Example 1. Immunovenin (25.0 ml intravenously every other day, for a course of 2-3 injections) was used for immunotherapy against the background of traditional conventional treatment of 50 patients suffering from purulent-septic diseases and being treated at the Republican Clinical Hospital named after G.G. Kuvatova (RKB) in the antiseptic center. Grade G serum Ig (IgG) was evaluated before and after immunotherapy. Then, the clinical efficacy of treatment was evaluated in patients in the group with an increase and in the group with a decrease in the initial level of IgG during immunotherapy. It was found that the best clinical efficacy (a shorter period of postoperative hyperthermia, a shorter hospital stay, a greater proportion of patients with recovery after treatment) was observed in the group with an increase in the initial IgG values on the background of immunotherapy with immuno-venin. The possible maximum IgG value for this group of patients with a 95.5% confidence probability was 13.90 g / l. Thus, the use of immunovenin for the purpose of immunotherapy to obtain the best treatment results is advisable at an IgG level detected by a preliminary examination of a patient with purulent-septic pathology, less than 13.90 g / l. The use of immunovenin with large initial IgG values will lead not to growth but to a decrease in the content of IgG, which will help to reduce the quality of treatment.

Example 2. Human leukocyte interferon (in suppository form at 10,000 IU per day, rectally, course - 10 suppositories) was used for immunotherapy against the background of traditional conventional treatment of 45 patients suffering from purulent-septic diseases and being treated in the antiseptic center of the RCH. The content of CD3 lymphocytes was evaluated before and after the completion of the course of immunotherapy. Then, the clinical efficacy of treatment was evaluated in patients in the group with an increase and in the group with a decrease in the initial level of CD3 lymphocytes during immunotherapy. It was established that the best clinical efficacy (a shorter period of postoperative hyperthermia, a shorter hospital stay, a greater proportion of patients with recovery after treatment) was observed in the group with an increase in the initial values of CD3 lymphocytes during immunotherapy with interferon. The possible maximum value of CD3 lymphocytes for this group of patients with a 95.5% confidence probability was 0.74 · 10 ⁹ / L. Thus, the use of interferon for the purpose of immunotherapy to obtain the best treatment results is advisable when the level of CD3 lymphocytes detected by a preliminary examination of a patient with purulent-septic pathology is less than 0.74 · 10 ⁹ / L. The use of interferon at high initial values of CD3 lymphocytes will lead not to growth but to a decrease in the content of CD3 lymphocytes, which will contribute to a decrease in the quality of treatment.

Example 3. For the purpose of immunotherapy, we used human leukocyte interferon - suppositoferon (in the form of a suppository of 10,000 ME per day, rectally, a course of 10 suppositories) against the background of the traditional conventional treatment of 45 patients suffering from purulent-inflammatory diseases and being treated in the antiseptic center of the Republic of Belarus . Class G serum immunoglobulin (IgG) was evaluated before and after the completion of the course of immunotherapy. Then, the clinical efficacy of treatment was evaluated in patients in the group with an increase and in the group with a decrease in the initial level of IgG during immunotherapy. It was found that the best clinical efficacy (a shorter period of postoperative hyperthermia, a shorter hospital stay, a number of reoperations, a higher level of recovered patients) was observed in the group with a decrease in the initial level of IgG on the background of interferon immunotherapy. Consequently, the use of interferon for immunotherapy in the treatment of purulent-inflammatory diseases proved to be most effective in patients in the group with an IgG level of (18.80 ± 1.80) g / l. Conversely, the worst clinical efficacy of interferon was observed in patients in the group with an IgG level (14.94 ± 0.64) g / l, which was accompanied by treatment with an increase in the initial IgG level.

The next step is to calculate the V _{min of the} initial IgG level in the group, where subsequent therapy is accompanied by better clinical outcomes and a decrease in its level:

V _min = M-2m = 18.80- (2 × 1.80) = 15.20 (g / l)

Thus, the use of interferon in the complex treatment of purulent-inflammatory pathology is advisable with an initial IgG level of more than 15.20 g / l. This will be accompanied by a subsequent decrease in IgG content and better clinical dynamics and disease outcomes compared with the group where treatment is accompanied by an increase in IgG levels. The use of interferon with a lower initial level of IgG will lead not to a decrease, but to an increase in IgG, which will contribute to a decrease in the quality of treatment.

Example 4. Ceruloplasmin (in the form of intravenous administration per 200 ml of 5% glucose solution or isotonic sodium chloride solution, at a dose of 100 mg of the drug per day, every other day, immediately after surgery, for the course of administration 2) was used for immunotherapy against the background of the traditional the generally accepted treatment of 59 patients suffering from purulent-inflammatory diseases and being treated in the RCH in the antiseptic center. The content of CD3 ⁺ lymphocytes in the blood was evaluated before and after the completion of the course of immunotherapy. Then, the clinical efficacy of treatment was evaluated in patients in the group with an increase and in the group with a decrease in the initial level of CD3 ⁺ lymphocytes during immunotherapy. It was found that the best clinical efficacy (a shorter period of postoperative hyperthermia, a shorter hospital stay, fewer reoperations and better outcomes in the form of a larger number of recovered patients) was observed in the group with an increase in the initial level of CD3 ⁺ lymphocytes during ceruloplasmin immunotherapy. Therefore, the use of ceruloplasmin for immunotherapy in the treatment of purulent-inflammatory diseases proved to be most effective in patients in the group with CD3 ⁺ lymphocytes (0.86 ± 0.05) × 10 ⁹ / L. Conversely, the worst clinical efficacy of ceruloplasmin was observed in patients in the group with CD3 ⁺ lymphocytes (1.13 ± 0.05) × 10 ⁹ / L, which was accompanied by a decrease in the initial content of CD3 ⁺ lymphocytes during treatment.

The next step is to calculate the V _{max of the} initial level of CD3 ⁺ lymphocytes in the group, where subsequent therapy is accompanied by better clinical outcomes and an increase in the content of CD3 ⁺ lymphocytes:

V _max = M + 2m = 0.86 + (2 × 0.05) = 0.96 (× 10 ⁹ / L),

where V _max - the possible maximum value of the indicator with a 95.5% confidence probability;

M - arithmetic mean;

m is the average error of the arithmetic mean.

Thus, the use of ceruloplasmin in the complex treatment of purulent-inflammatory pathology is advisable when the initial level of CD3 ⁺ lymphocytes is less than 0.96 × 10 ⁹ / L. This will be accompanied by a subsequent increase in the content of CD3 ⁺ lymphocytes and better clinical dynamics and outcomes of the disease in comparison with the group where treatment is accompanied by a decrease in the level of CD3 ⁺ lymphocytes.

Claims (1)

A method for selecting criteria for adequate immunotherapy for purulent-inflammatory diseases, including determining immunological parameters before and after using an immunomodulator against the background of conventional treatment, characterized in that the level of IgG or CD3 lymphocytes is determined, a group of patients with an increase and a group with a decrease in the value of immunological indicator against immunotherapy, conduct a comparative assessment of the clinical effectiveness of treatment, namely, the duration of hospitalization, hyperthermia, the number Twa reoperation, disease outcome in patients in these groups and if the best clinical efficacy achieved in the group with increasing consideration immunological indicator, determine the maximum value of immunological parameters in the group prior to immunotherapy (V _max), when the initial value finding immunological patient index below the established maximum value of this indicator in the group, the use of this immunomodulator is considered most appropriate if the highest clinical efficacy was achieved in the group with a decrease in the immunological indicator under consideration, the possible minimum value of this immunological indicator in the group before the start of immunotherapy (V _min ) is determined, when the patient’s initial immunological indicator is higher than the established maximum value of this indicator in the group, the use of this immunomodulator is considered the most rational, V _max and V _{min are} defined as the upper and lower bounds of the indicator value, respectively group of patients with a 95.5% confidence probability.