RU2340902C1 - Method of diagnostics of seriousness of inflammatory process at bacteriemic purulent meningitis at children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns area of medicine and can be used for diagnostics of seriousness of inflammatory process at a bacteriemic purulent meningitis at children. In CSG after centrifugation with the immuno turbidimetry method define concentration of an alpha 2 - macroglobulin. At its maintenance of 0.7-2.9 mg/dl - diagnose an intermediate inflammation, at 3.0-8.0 mg/dl - serious, and at concentration over 8.1 mg/dl - an extremely serious. Use of the method allows to increase accuracy of diagnostics of seriousness of inflammatory process at bacteriemic purulent meningitis at children that allows to increase efficiency of performed treatment.

EFFECT: increase of accuracy of diagnostics of gravity of inflammatory process at a bacteriemic purulent meningitis at children that allows to increase efficiency of spent treatment.

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Description

This invention relates to medicine, namely to clinical and laboratory methods for diagnosing neuroinfectious diseases, and can be used to diagnose the severity of the inflammatory process in the nervous tissue in bacterial purulent meningitis (BGM) in children.

The urgency of the problem of BGM in children is due to the high frequency of development of complicated forms (in 1/3 of cases), mortality (up to 30%) and the presence of residual neurological consequences in 15-30%. In this regard, a timely and objective assessment of the severity of the inflammatory process in the membranes and brain tissue is relevant for improving the diagnosis and treatment results of HMD in children.

Until now, the main criterion for assessing the severity of the inflammatory process in the nervous tissue remains a clinical and neurological examination and the results of the analysis of cerebrospinal fluid (CSF) obtained by diagnostic lumbar puncture (Guide to Infectious Diseases / Ed. Corresponding Member of RAMS, prof. Yu.V. Lobzina .-- St. Petersburg: Tome, 2000 .-- 936 p.).

A well-known clinical indicator of the severity of the inflammatory process with BGM is the degree of impaired consciousness, the presence of focal symptoms and the severity of the meningeal symptom complex (Mikhailenko A.A., Pokrovsky V.I. Edema-swelling of the brain in coma in infectious patients. - M .: Medicine, 1997 .-- 384 p.). However, the assessment of neurological status is subjective in nature, and impaired consciousness can be a consequence not only of the severity of the inflammatory process in the brain tissue, but also the result of exposure to the state of the brain of toxic products and products of impaired metabolism (“metabolic coma”). The study of the composition of CSF by standard methods (total protein content, cytosis) allows you to diagnose a neuroinfection process, however, there is no direct relationship between the increase in these indicators and the severity of the inflammatory process in the brain tissue. In addition to the generally accepted study of cerebrospinal fluid, it can be fractionated by polyacrylamide gel electrophoresis (L.A. Alekseeva, N.V. Skripchenko, V.V. Karasev, T.V. Bessonova, Ivanova M.V. -peptide composition of cerebrospinal fluid for the diagnosis and prognosis of bacterial purulent meningitis in children / Epidemiology and Infectious Diseases 2005. - No. 3. - P.50-54). It was found that the degree of increase in certain protein fractions correlates with the severity of brain damage and the leading pathogenetic mechanism of the complicated course of BGM. However, the use of this method is time-consuming, lengthy and does not allow for the rapid determination of individual liquor proteins with high accuracy, which complicates the diagnosis of BGM in children.

Closest to the proposed method is a method for predicting the course and outcomes of BGM in children based on the study of the levels of high molecular and low molecular weight components of cerebrospinal fluid during its fractionation by gel filtration on Sephadex G-50 (Sorokina M.N., Alekseeva L.A. bacterial meningitis // In the book Bacterial meningitis in children. - M .: Medicine, 2003. - P.108-127). This method allows a comprehensive assessment of the composition of the cerebrospinal fluid, reflecting various aspects of pathogenesis, including not only the inflammatory process in the brain parenchyma, but also intoxication of the body. However, a quantitative assessment of pools of cerebrospinal fluid components of different origin does not allow one to diagnose the degree of the inflammatory process of the brain with sufficient accuracy and speed.

The technical result achieved by the invention is to increase the accuracy and speed up diagnosis, improving the effectiveness of the treatment by quantifying the level of alpha 2-macroglobulin (alpha 2-MG) in CSF.

The invention consists in achieving the technical result in a method for diagnosing the severity of the inflammatory process in bacterial purulent meningitis in children, which involves a biochemical study of the protein composition of cerebrospinal fluid, according to the invention, the concentration of alpha 2-macroglobulin is determined by immunoturbidimetric analysis and its content is: 0.7 -2.9 mg / dl diagnose moderate inflammation of the brain, at a concentration of 3.0-8.0 mg / dl - severe, and concentrations above 8.1 mg / dl are extremely severe.

A significant difference of this method is the determination of alpha 2-macroglobulin in CSF using immunoturbidimetric analysis. The authors, using this indicator for the first time, were able to prove by clinical and biochemical comparisons on a group of patients that its determination in CSF is an effective diagnostic method for assessing the severity of the inflammatory process in the nervous tissue in patients with BGM, which allows, based on the data obtained, to timely correct therapy. The authors for the first time experimentally on a group of 47 patients established ranges characteristic for moderate, severe and extremely severe inflammatory processes in the nervous tissue (Table 1).

Table 1 The content of alpha 2-macroglobulin in cerebrospinal fluid in bacterial purulent meningitis in children with different severity of the inflammatory process. Groups of patients with varying severity of brain inflammation Number of patients Alpha concentration 2-MG (mg / dl) (Chr. ± m) Limits of fluctuation of alpha 2-MG in groups (mg / dl) Moderate inflammation eleven 1.84 ± 0.26 ^x 0.7-2.9 Severe inflammation 21 4.91 ± 0.63 ^ho 3.0-8.0 Extremely severe inflammation fifteen 10.8 ± 1.3 ^{x0 *} > 8.1 The control 10 0.34 ± 0.08 0,0-0,70 x - differences are significant compared with the control
0 - differences are significant compared with moderate severity of brain inflammation
* - the differences are significant compared with a severe degree of inflammation of the brain

At a concentration of alpha 2-MG in the range of 0.7-2.9 mg / dl, moderate brain inflammation is diagnosed, characterized by intoxication, meningeal symptoms, moderate neutrophilic pleocytosis (up to 1000 × 10 ⁶ / L), lack of impaired consciousness and focal symptoms. When the alpha 2-MG value is in the range of 3.0-8.0 mg / dl, the degree of inflammation of the nervous tissue is assessed as severe, characterized by severe intoxication, meningeal symptoms, increased intracranial pressure, transient focal neurological symptoms, severe pleocytosis, reaching 10,000 × 10 ⁶ / l With an alpha 2-MG concentration of more than 8.1 mg / dl, the degree of inflammation of the cerebral parenchyma is extremely severe with impaired consciousness, focal symptoms of central nervous system damage, and the formation of pronounced residual consequences.

Thus, as a result of the expansion of the spectrum of CSF studies and the inclusion of a new biochemical indicator (alpha 2-MG) reflecting the degree of impaired permeability of the blood-brain barrier in the analysis of cause-effect relationships, new possibilities have been revealed for improving the diagnosis and treatment results of patients with BGM.

The method is as follows. When a patient is admitted with a suspicion of BGM, lumbar puncture is performed and 1-2 ml of cerebrospinal fluid is taken for analysis. Part of the cerebrospinal fluid is examined in a standard way, determining the total protein content and pleocytosis with differentiation of cellular elements. The remainder of the cerebrospinal fluid is centrifuged at 1500 rpm for 20 minutes and the concentration of alpha 2-MG is determined in a centrifugate by immunoturbidimetry using kits from Sentinel (Italy). The principle of the method is based on the reaction between alpha 2-MG as an antigen and a specific antiserum as an antibody. Given that the concentration of proteins in CSF is 100-200 times lower than in blood serum, cerebrospinal fluid samples are not diluted before the study. Calculation of alpha 2-MG concentration is carried out according to a calibration curve previously constructed from the results of measuring the optical density of various dilutions of a standard protein solution (protein calibrator). The authors for the first time worked out the conditions and possibilities for determining alpha 2-MG in CSF in children with hypertension. The data obtained by the authors on the concentration of alpha 2-MG in the cerebrospinal fluid of children with bacterial purulent meningitis allow, within a short time (30-40 minutes), using only 50 μl of CSF, additional information on the biochemical composition of CSF reflecting the degree of impaired blood-brain barrier permeability ( BBB), and, therefore, about the degree of inflammation of the cerebral parenchyma.

A method for diagnosing the severity of the inflammatory process in the nervous tissue in children with BGM was developed at the Research Institute for Children's Infections and passed clinical trials during the examination and treatment of 47 patients aged 2 months to 16 years. Among the examined patients, meningococcal meningitis was diagnosed in 28, hemophilic - in 12, pneumococcal - in 2 patients, unclear etiology - in 5 patients. According to the severity of the inflammatory process of the cerebral parenchyma in the acute period of the disease, assessed by the severity of meningeal and focal symptoms, the degree of impaired consciousness, data from an electrophysiological and clinical laboratory examination, the patients were divided into 3 groups. In patients with moderate form of BGM (group 1), in the acute period, there was no impairment of consciousness, there was no focal neurological symptomatology, the shell syndrome was significantly shorter (Table 2).

table 2 The duration of the main clinical symptoms in groups of children with varying degrees of inflammation of the nervous tissue in bacterial purulent meningitis. Patient groups Number of patients Symptoms The degree of pleocytosis (× 10 ⁶ / l) Impaired consciousness Meningeal syndrome Focal symptoms Moderate inflammation eleven 1000 ± 120 0 4.3 ± 0.6 0 Severe inflammation 21 10000 ± 320 2.1 ± 0.2 ⁰ 7.3 ± 1.6 4.7 ± 0.7 ⁰ Extremely severe inflammation fifteen > 10,000 5.9 ± 0.9 ⁰ * 11 ± 1.8 16.4 ± 1.2 ^{0 *} 0 - differences are significant compared with moderate severity of brain inflammation
* - the differences are significant compared with a severe degree of inflammation of the brain

During convalescence in patients of the first group, no neurological abnormalities were detected (Table 3).

Table 3 Outcomes of the disease with bacterial purulent meningitis in children with varying severity. Groups of patients with various severity of BGM The number of patients in groups The number of patients with residual consequences: absolute % Moderate inflammation eleven 0 0 Severe inflammation 21 3 fifteen Extremely severe inflammation fifteen 10 70

In patients of the second group in the acute period of the disease in 20% of cases there was impaired consciousness without a transition to a coma, a more pronounced and prolonged meningeal syndrome, manifestations of transient focal neurological symptoms (in 20%). Persistent neurological complications in patients of this group by the period of convalescence did not form. Only 15% showed residual consequences in the form of asthenoneurotic syndrome. An extremely severe degree of inflammation of the cerebral parenchyma (group 3) was characterized by severe impairment of consciousness in 90% of patients, prolonged meningeal syndrome, severe focal symptoms in 75% of cases, coma was noted in 50% of patients. 70% of the convalescents of this group retained focal symptoms, leading to severe neurological deficit. Studies in dynamics confirmed the correctness of the diagnosis, revealing significantly longer periods of preservation of meningeal and focal symptoms, as well as the frequency and severity of residual neurological consequences in the stage of convalescence, depending on the severity of the inflammatory process in the acute period of the disease (Table 2.3). As a control, CSF samples of convalescents of meningococcal meningitis with normal standard indicators of cerebrospinal fluid (total protein, cytosis) without pronounced deviations in neurological and somatic status were studied.

To confirm the effectiveness of the method, we give examples - extracts from medical records.

Example 1. Patient P., 8 months. Case history No. 1325, the diagnosis is a generalized form of meningococcal infection, meningococcemia, purulent meningitis. He fell ill acutely, there was a sharp rise in temperature to 39.5 degrees, a headache, the appearance of a hemorrhagic rash. Hospitalized in NIIDI on the first day of the disease. Upon receipt, the condition is serious. At a neurological examination - moderate severity of shell symptoms (stiff neck (+), Kernig symptom (+),) focal neurological symptoms are absent. Analysis of cerebrospinal fluid (CSF) - cytosis 2714 × 10 ⁶ / l, total protein 0.35 g / l. A quantitative study of the content of alpha 2-MG (0.71 mg / dl) corresponds to a moderate degree of inflammation of the cerebral parenchyma. Repeated lumbar puncture was performed on the 7th day: protein - 0.2 g / l, cytosis - 21 × 10 ⁶ / l, alpha 2-MG concentration - 0.48 mg / dl. In the clinical picture, a regression of shell symptoms was observed on the 3rd day of the disease. The patient received standard treatment, dehydration. Thus, the degree of inflammation of the cerebral parenchyma diagnosed in the acute period of the disease in terms of alpha 2-MG corresponded to the clinical picture, the moderate course of the disease and a favorable outcome.

Example 2. Patient L., 1 year 6 months. Case history No. 4924, the diagnosis is a generalized form of meningococcal infection, meningococcemia, purulent meningitis. He fell ill acutely, fever up to 39 degrees, 9 times vomiting, restlessness, trembling, a hemorrhagic rash appeared on his left thigh. Hospitalized in NIIDI on the first day of the disease. Upon admission, the condition is serious, consciousness at the level of stupor. Focal neurological symptoms are absent, pronounced shell symptoms are noted: stiff neck (+++), Kernig symptom (+++). In the analysis of CSF - cytosis - 5547 × 10 ⁶ / l, protein - 2.13 g / l. The content of alpha 2-MG in CSF is 4.76 mg / dl, which corresponds to a severe degree of inflammation of the brain. The patient received intensive care, including dehydration, infusion therapy, antibiotic treatment. The time spent in the intensive care unit is 24 hours. Studies in dynamics (on the 10th day) revealed positive changes in the composition of the cerebrospinal fluid: cytosis - 24 × 10 ⁶ / l, protein - 0.44 g / l, alpha 2-MG content in CSF - 1.19 mg / dl. The patient was discharged without residual consequences. The duration of meningeal symptoms compared with the previous example is doubled (6 days). Thus, the concentration of alpha 2-MG in the acute period of the disease corresponded to a severe degree of inflammation of the cerebral parenchyma, which was confirmed not only by the severity of meningeal symptoms at the time of the examination, but also by their longer duration compared to example 1. The degree of inflammatory changes in the brain the parenchyma corresponded to the severity of the condition at the time of admission and correlated with the severity of cerebral symptoms.

Example 3. Patient K., 1 year. Case history No. 2288, the diagnosis is a generalized form of hemophilic infection, purulent meningitis, cerebral edema, convulsive syndrome, acute myocardial dystrophy. He entered the intensive care unit of NIIDI on the first day of the disease. He fell ill acutely, there was an increase in body temperature up to 38 degrees, repeated vomiting, attacks of tonic-clonic seizures. Upon admission, the condition is extremely serious: the level of consciousness is coma 2, stem disorders in the form of divergent strabismus, narrow pupils. Despite drug sedation, convulsions, diffuse muscle hypotension, and severe microcirculation disorders were noted. Shell symptoms are mild. CSF study: cytosis - 3386 × 10 ⁶ l, total protein - 1.94 g / l, alpha 2-MG in CSF - 9.76 mg / dl, which reflects an extremely severe degree of inflammation of the cerebral parenchyma. In treatment, in addition to the main therapy, hormone therapy, vasopressors, anticonvulsants were used. The child was discharged 38 days after the onset of the disease.

Example 4 illustrates the significance of our proposed method in assessing the degree of inflammation of the cerebral parenchyma. Patient G., 2 years 7 months, medical history No. 5726, diagnosis - generalized form of meningococcal infection, purulent meningitis. He fell ill acutely, there was an increase in body temperature up to 39 degrees, double vomiting, hemorrhagic rash. With a suspected meningococcal infection, the child was hospitalized at NIIDI on the first day of the disease. Upon receipt, the condition is serious, in the mind, complaints of a headache. At the time of examination, focal symptoms were not noted, shell symptoms were slightly expressed: REM (+), Kernig (+). In the analysis of CSF - cytosis 925 × 10 ⁶ / l, total protein - 0.26, which is typical for moderate inflammation. In contrast to the results of a standard CSF study, the data of immunoturbidimetric determination of alpha 2-MG indicated an extremely severe degree of the inflammatory process of the cerebral parenchyma (alpha concentration of 2-MG is 10.0 mg / dl). Within a day after admission, the patient received standard treatment: dehydration, infusion therapy. However, on the second day of the disease, focal symptoms appeared in the form of severe ataxia, left-side hemiparesis, which required hormone therapy, and the appointment of antihypoxants. When examining CSF on day 3, the following results were obtained, cytosis - 23 × 10 ⁶ / l, protein - 0.4 g / l, alpha 2-MG concentration - 3.1 mg / dl. Thus, despite the fact that clinically on the first day of the disease the degree of brain inflammation was assessed as moderate, a study of the concentration of alpha 2-MG indicated an extremely severe degree of inflammation, which was confirmed by the complicated course of the disease and required a significant correction of therapy. After 20 days in the hospital, the patient was discharged.

Thus, the above examples illustrate the possibility of using the proposed method as an objective quantitative criterion, which allows to diagnose the severity of brain inflammation in children with hypertension in the early stages with the aim of timely correction of therapy. The proposed method improves the accuracy and objectivity of diagnosis, accelerates the time of its implementation, which helps to improve treatment and reduce the length of stay of the patient in the clinic. Given the correlation between clinical symptoms and the concentration of alpha 2-MG, studied using the method of immunoturbidimetric analysis, it is possible to develop an appropriate correction of therapy, determined on this basis. So, if in group 1 (moderate inflammation of the cerebral parenchyma) adequate use of standard antibiotics and infusion therapy are sufficient, then in group 2 (severe inflammation) it is necessary to use broad-spectrum antibiotics, antihypoxants, additional detoxification therapy, active dehydration, and in the 3rd (extremely severe inflammation) - mechanical ventilation in combination with broad-spectrum antibiotics and complex therapy (hormones, antihypoxants, immune plasma and leukemia suspension ) aimed at stopping cerebral symptoms.

Claims (1)

A method for diagnosing the severity of the inflammatory process in bacterial purulent meningitis in children by biochemical study of the protein composition of cerebrospinal fluid, characterized in that in the CSF after centrifugation by immunoturbidimetry, the concentration of alpha 2-macroglobulin is determined and its content: 0.7-2.9 mg / dl they diagnose moderate inflammation, at 3.0-8.0 mg / dl - severe, and at a concentration of more than 8.1 mg / dl - extremely severe.