RU2665945C1 - Method for predicting the duration of the diarrhea and the selection of tactics of treatment - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to the field of medicine, namely to infectious diseases, and can be used to select treatment tactics in patients with acute intestinal infections (AII). Method includes the administration of Galavit in addition to standard etiotropic and pathogenetic therapy, with the content of intestinal interleukin-6 (IL-6) in the coprofilter prior to initiation of therapy. At the level of intestinal IL-6, 1–18 pg/ml predict short-term diarrhea: for 1–3 days, with no therapy Galavit. At the level of IL-6, 19–25 pg/mg predict prolonged diarrhea in patients: from 4 to 10 days, while prescribing Galavit sublingually in a dose of 2 tablets once and then 1 tablet 4 times a day for 4–5 days.EFFECT: use of the invention makes it possible to improve the accuracy of the prognosis in the early stages of the disease, personify Galavit's appointment to patients with acute intestinal infections and predicted protracted course of the disease, reduce the duration of diarrhea and the duration of general symptoms of the disease.1 cl, 2 tbl, 4 ex

Description

The present invention relates to medicine, namely to infectious diseases, and can be used to select treatment tactics in patients with acute intestinal infections, depending on the predicted duration of diarrhea.

Despite the achievements of modern medicine, the main place in the structure of the infectious is occupied by acute intestinal infections (AEI). Every year in Russia, a high incidence of acute intestinal infections is recorded, reaching 500-550 cases per 100,000 population, of which more than 60% remain etiologically not deciphered [1].

Non-specific peptide mediators of the immune system, such as cytokines, can tell about the state of local intestinal resistance [2, 3, 4]. A study of the level of pro-inflammatory cytokines in coprofiltrates, including interleukin-6, demonstrated the feasibility of their use for assessing the severity and prognosis of various ACIs [5, 6, 7].

A significant impact on the functioning of the cytokine system is exerted by many biologically active substances, such as immunomodulators, among which Galavit is not the last. In clinical studies conducted earlier, Galavit's ability to increase the functional activity of macrophages, the synthesis of interferons and lysozyme, regulate the balance of pro-inflammatory and anti-inflammatory cytokines in the blood serum, and increase the sensitivity of opportunistic intestinal flora to antibacterial drugs was proved [8, 9, 10]. When modeling intestinal infection in an experiment and conducting clinical studies, a normalizing effect of Galavit was noted not only on the intestinal microbiota, but also on its functional state, due to the suppression of the activity of intestinal anti-inflammatory and stimulation of the synthesis of intestinal anti-inflammatory cytokines [7, 11, 12].

A number of methods are known for assessing the forecast of the OKI course. So, a method for predicting the course of OCI is described, based on determining the degree of endotoxin binding by gram-negative bacteria using the FC-dependent mechanism (V.G. Likhoded, I.A. Anikhovskaya et al. FC-dependent binding of gram-negative bacteria endotoxins by human polymorphonuclear leukocytes // J. Microbiol., 1996, No. 2, pp. 76-79) [13]. This method allows you to predict the course of OCI caused only by gram-negative bacteria. Meanwhile, at present, 30-60% of all cases of acute intestinal infections are caused by viruses, and acute respiratory infections associated with gram-positive flora are also common.

There is also a method for predicting acute intestinal infections in children (RU 2275634, class G01N 33/52/66 publ. 04/27/2006) [14], the essence of which is that in the smears of blood samples stained with acridine orange, calculate the ratio the number of polymorphonuclear leukocytes with single-stranded RNA to the number of polymorphic nuclear leukocytes with double-stranded DNA before (k) and after (°) treatment with endotoxin, the index of the ratio ° to k is determined and, if it is greater than or equal to unity, a prolonged course of acute intestinal tract is predicted infection. The disadvantages of this method are its complexity, the use of a limited age population, only an indirect assessment of the state of the gastrointestinal tract based on peripheral blood parameters.

The literature also contains a description of the method for predicting the course of the disease in patients with salmonellosis and acute shigellosis based on serum cytokine levels (IL-1, IL-10, TNF-α) and blood gas composition. This method involves a comprehensive assessment of the level of pro- and anti-inflammatory cytokines, but, nevertheless, is based on the determination of their concentration in the blood, which allows only a rough estimate of the state of the gastrointestinal tract. In addition, this method is focused only on salmonellosis and shigellosis and does not imply its use in other nosologies [15].

Another significant drawback of all the above methods is the absence of any recommendations for optimizing the treatment of acute intestinal infections based on prediction of a protracted course of the disease.

The closest analogue to the proposed invention is a method for the treatment of patients with acute intestinal infections using Galavita (Nagoyev BS, et al., 1999) [9]. Galavit was administered 200 mg (initial dose) intramuscularly, then twice with a 5-hour interval of 100 mg. The drug was prescribed only to patients with moderate and severe forms of acute intestinal infections, which were established upon admission only on the basis of clinical data - severe symptoms of intoxication and diarrhea. Various clinical manifestations of acute intestinal infections in patients were leveled within 1-6 days of illness, in the control group within 3-8 days.

The disadvantage of this method is that the drug was administered intramuscularly. This increased the risk of developing phlegmon and abscesses in the area of its administration. In addition, moderate and severe forms of acute intestinal infections (i.e., those forms of the disease in which a prolonged course of diarrhea is usually predicted and which are the basis for prescribing the drug) were established only on the basis of the clinical manifestations of the disease on day 1-2 of the disease. Meanwhile, in the early stages of the disease, it is difficult to predict the protracted nature of diarrhea only by the clinical manifestations of acute intestinal infections. It can be short-term at the onset of the disease with high fever and severe dyspeptic manifestations, and, conversely, with unexpressed manifestations of general intoxication, become protracted and last up to 8-10 days or more.

To eliminate the above drawbacks, the authors propose a method for predicting the duration of diarrhea and choosing treatment tactics for patients with acute intestinal infections receiving standard etiotropic and pathogenetic therapy, depending on the predicted duration of diarrhea, and based on the selective prescription of Galavit, in patients with acute respiratory infections depending on the level of intestinal interleukin-6 IL-6) in the acute period of the disease.

The technical result of the invention is to increase the accuracy of the prognosis in the early stages of the disease, in the personified appointment of Galavit to patients with acute intestinal infections who are expected to have a prolonged course of the disease, in reducing the duration of diarrhea and the duration of the general symptoms of the disease.

This object is achieved in that a method for predicting the duration of diarrhea and choosing treatment tactics includes the appointment of Galavit in addition to standard etiotropic and pathogenetic therapy.

In accordance with the invention, before the start of therapy, the content of intestinal interleukin-6 (IL-6) in coprofiltrate is determined in patients, and

- at the level of intestinal IL-6 1-18 pg / ml, short-term diarrhea is predicted: for 1-3 days, while Galavit therapy is not carried out, and

- at an IL-6 level of 19-25 pg / mg, prolonged diarrhea is predicted in patients: from 4 to 10 days, while Galavit is prescribed sublingually in a dose of 2 tablets once and then 1 tablet 4 times a day for 4-5 days.

Under our supervision, at the 1st stage of the study, there were 58 patients with AKI aged 18-65 years. Patients with severe somatic pathology, concomitant diseases of the gastrointestinal tract in the acute stage, the presence of veins or impurities of blood in the feces, the duration of the disease for more than 48 hours, and a history of any therapy using antibacterial drugs were excluded from the study. Material was taken from the rectum on the day of admission, on the 1st day of illness, before the start of therapy with dacron sterile swab probes, collecting material from the intestinal crypts. After extraction, the tampon was immersed in the Keri Blair transport medium and delivered to the laboratory. The level of IL-6 was determined using commercial kits "Vector-best" in coprofiltrates.

In the course of our study, it was found: with a duration of diarrhea of 1-4 days, the level of intestinal IL-6 was: 1-18 pg / mg in 90.0% of cases, with a duration of diarrhea of 5-10 days, the level of IL-6 was 19-25pg / mg in 92.3% of cases.

The sensitivity, specificity and prognostic value of the method for predicting the duration of diarrhea was determined based on the fact that:

and (truly positive results) - the predicted short-term diarrhea of 1-4 days on the basis of IL-6 indices of 1-18 pg / mg actually corresponded to that in 27 patients;

b (false positive results) - the predicted duration of diarrhea in 4-10 days in accordance with the indicators of IL-6 19-25 pg / mg, in fact, was in the range of 1-4 days - in 2 patients;

c (false negative results) - the predicted duration of diarrhea in 1-4 days in accordance with the indicators of IL-6 1-18 pg / mg, in fact, was in the range of 5-10 days - in 3 patients;

d (true negative) - diarrhea could not be regarded as short-term, according to IL-6 indices of 19-25 pg / mg, and in fact turned out to be prolonged with a duration in the range of 5-10 days - in 26 patients

Sensitivity = a / (a + s) * 100% = 27 (27 + 3) * 100% = 90%

Specificity = d / (b + d) * 100% = 26 (2 + 26)) * 100% = 92.3%

Predicted value = a / (a + b) * 100% = 27 / (27 + 2) = 93.1%

At the 2nd stage of the study, 100 patients were recruited based on the inclusion / exclusion criteria similar to the 1st stage, of which 2 groups of patients were formed on the basis of the level of intestinal IL-6 determined upon admission. The 1st group (48 people) included patients with an IL-6 level of 1-18 pg / mg, the 2nd group (52 people) included patients with an IL-6 level of 19-25 pg / mg. Further, each of the groups was randomized into 2 equal subgroups - 1A and 1B, 2A and 2B, respectively.

All patients of subgroups 1A and 2A received standard conventional rehydration therapy, enterosorbents, antispasmodics, metoclopramide (according to indications), and probiotics from day 4-5 of the disease. Antibiotics were prescribed for fever for more than 2 days over 38.5 ° C in combination with symptoms of gastroenterocrolyte. From the moment of admission to the hospital, all patients of subgroups 1B and 2B were prescribed Galavit 2 tablets once sublingually and then 1 tablet 4 times a day for 4-5 days in addition to the standard therapy regimen. All patients signed informed consent to participate in the study. Statistical processing of the obtained data was performed using the SPSS Statistics 23.0 program.

The frequency of occurrence of the main clinical symptoms upon admission to hospital in subgroups 1A and 1B, in which the level of IL-6 was in the range of 1-18 pg / ml, as well as in subgroups 2A and 2B, in which the level of IL-6 was in the range of 19-25 pg / ml was statistically equivalent (Table 1).

The duration of the disease symptoms during therapy did not have a statistically significant difference when comparing subgroup 1A, whose patients did not receive Galavit, with subgroup 1B, to whose patients this drug was prescribed (Table 2). Thus, the appointment of Galavit at an intestinal IL-6 level of 1-18 pg / ml did not have any significant effect on the duration of the symptoms of the disease.

Meanwhile, when comparing the dynamics of leveling of symptoms in subgroups in which the level of intestinal IL-6 was 19-25 pg / ml, namely 2A (without Galavit) and 2B (with Galavit), significant differences were found. They consisted of a statistically significant reduction in the duration of the main symptoms of the disease - fever, diarrhea, and others (Table 2).

Thus, we can conclude that the clinical efficacy of Galavit was manifested in patients with acute intestinal infections with an intestinal EL-6 level of 19-25 pg / ml, that is, with pronounced inflammatory changes in the intestine, which can be directly judged by the indices of IL-6 from the local focus inflammatory process in the intestines. Its appointment at the level of intestinal IL-6 in the range of 1-18 pg / ml did not have a significant clinical effect.

The results of the study also allow us to recommend the appointment of Galavit in acute intestinal infections according to the aforementioned scheme with indicators of intestinal IL-6 in the range of 19-25 pg / ml, which can predict a prolonged course of diarrhea.

The invention is illustrated by the following clinical examples from the studied groups.

Example 1. Patient I., 19 years old (subgroup 1A), was hospitalized in the infectious diseases hospital on 05/20/2014 with complaints of: nausea, single vomiting, 4-fold loose stool without pathological impurities. He was ill for 11 hours at the time of admission. Body temperature at admission 36.8 ° C. The patient was diagnosed with OCI (gastroenteritis). The level of IL-6 in coprofiltrate was 6 pg / ml. The degree of risk of a protracted course of diarrhea was regarded as low. The therapy was prescribed: diet No. 5, Trisol solution 1200 ml intravenously drip once a day for 1 day; Regidron 400-600 ml during the 2nd and 3rd day of illness; Polysorb 3 g 4 times a day for 4 days. Galavit was not appointed. During treatment, the patient's condition progressively improved. Patient I. was discharged from the hospital on the 4th day of hospitalization in satisfactory condition. This example is evidence that the level of IL-6 determined at an early stage of the disease made it possible to make a subsequently confirmed forecast of a low risk of developing a protracted course of diarrhea and to choose the appropriate treatment tactics.

Example 2. Patient A., 30 years old (subgroup 2A), was hospitalized in the infectious diseases hospital on July 15, 2014 with complaints of: nausea, 3-fold vomiting, 10-fold loose stool with an admixture of mucus. At the time of admission, she was ill for 20 hours. Body temperature at admission 37.7 ° C. The patient was diagnosed with OCI (gastroenterocolitis). The level of IL-6 in feces was 24 pg / ml. The degree of risk of a protracted course of diarrhea was regarded as high.

Therapy was prescribed: diet No. 5, Trisol solution 1200 ml. intravenously drip once a day on the day of admission to the hospital; Ringer's solution 800 ml intravenously once a day from the 2nd to the 4th day of illness; Oralitis 400-600 ml from the 5th to the 7th day of illness. Polysorb 3 g. 4 times a day for 7 days; nifuroxazide 200 mg 4 times a day from the 2nd to the 6th day of illness; Bifiform 2 capsules 2 times a day from 5 to 11 days of illness. Galavit was not prescribed due to the fact that the patient was randomized to subgroup 2A, whose patients received only standard therapy. The patient's condition remained unchanged for 3 days, then, up to the 10th day of illness, a slow leveling of the symptoms of the disease was noted. Patient A. was discharged on the 10th day of hospitalization in satisfactory condition. This example is evidence that the established level of IL-6 made it possible to make a forecast come true subsequently about the high risk of developing a protracted course of diarrhea.

Example 3. Patient B., 38 years old (subgroup 1B), was hospitalized in the infectious diseases hospital on 07/07/2014 with complaints of: nausea, 2-time vomiting, 5-fold loose stool without pathological impurities. She was ill for 8 hours at the time of admission. Body temperature at admission 37.6 ° C. The patient was diagnosed with OCI (gastroenteritis). The level of IL-6 in coprofiltrate was 9 pg / ml. The degree of risk of a protracted course of diarrhea was regarded as low. Appointed therapy: diet No. 5, Ringer's solution of 1500 ml intravenously drip once a day on the 1st day of illness; Further, oral administration of Regidron 400-600 ml / day during the 2nd and 3rd day of illness. Polysorb 3 g 4 times a day for 3 days. Galavit 2 tablets once sublingually and then 1 tablet 4 times a day for 4 days, as the patient was included in subgroup 2B, all patients of which received Galavit in addition to standard therapy. Patient B. was discharged from the hospital on the 4th day of hospitalization in satisfactory condition.

This example is evidence that the IL-6 level established at the beginning of the disease made it possible to make a subsequently come true forecast of a low risk of developing a protracted course of diarrhea. Taking Galavit in a patient with a low risk of developing a prolonged course of diarrhea did not lead to a reduction in the duration of the disease compared with the patient from clinical example 1 with the same low risk of developing it, but not taking this drug.

Example 4. Patient S., 28 years old (subgroup 2B), was hospitalized in the infectious diseases hospital on 08/30/2014 with complaints of: nausea, 4-fold vomiting, 12-fold loose stool with an admixture of mucus. At the time of admission, he was ill for 25 hours. Body temperature at admission 38.5 ° C. The patient was diagnosed with OCI (gastroenterocolitis). The level of IL-6 in feces was 25 pg / ml. The degree of risk of a protracted course of diarrhea was regarded as high. Appointed therapy: Galavit 2 tablets once sublingually and then 1 tablet 4 times a day for 4 days. diet No. 5, Trisol solution 1200 ml. intravenously drip once a day on the 1st day of hospitalization; Ringer's solution 800 ml intravenously once a day from the 1st to the 3rd day of hospital stay; Polysorb 3 g. 4 times a day for 3 days; nifuroxazide 200 mg 4 times a day from the 2nd to the 5th day of illness. The patient's condition, initially regarded as moderate, began to progressively improve. Patient S. was discharged from the hospital on the 4th day of hospital stay (5th day of illness) in satisfactory condition. This example is evidence that the established level of IL-6 made it possible to make a forecast come true subsequently about the high risk of developing a protracted course of diarrhea. Reception of Galavit in a patient with a high risk of developing a protracted course of diarrhea led to a significant reduction in the duration of the disease compared with the patient from clinical example 2 with the same high risk of developing it, but not taking this drug.

The study and clinical examples clearly demonstrate the prognostic significance of determining the level of intestinal IL-6 in acute intestinal infections for predicting the protracted nature of diarrhea and the feasibility of using Galavit at an IL-6 level of 19-25 pg / ml.

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Claims (1)

A method for predicting the duration of diarrhea and the choice of treatment tactics, including the appointment of Galavit in addition to standard etiotropic and pathogenetic therapy, characterized in that before the start of therapy, the content of intestinal interleukin-6 (IL-6) in coprofiltrate and at the level of intestinal IL-6 are determined 1-18 pg / ml predict short-term diarrhea, for 1-3 days, while Galavit therapy is not carried out, and at an IL-6 level of 19-25 pg / mg prolonged diarrhea is predicted in patients from 4 to 10 days, and Galavit is prescribed sublingual dose 2 tablets once and then 1 tablet 4 times a day for 4-5 days.