Scientific Grounds for Pathogenetic Therapy of Bacterial Purulent Meningitis in Children

The dissertation by Makarova Tatyana Evgenievna is devoted to the scientific substantiation of pathogenetic therapy of bacterial purulent meningitis in children. The research is conducted on the materials of the children's infectious hospital of Khabarovsk and encompasses etiology, epidemiology, clinical manifestations, as well as pathogenetic mechanisms of the development of cerebral edema, disturbances of brain tissue metabolism, and immunological changes in these diseases. The study examines stages of cerebral edema using clinical, instrumental (reoencephalography, electroencephalography), and laboratory diagnostic methods. Based on the conducted research, the use of additional methods of pathogenetic therapy aimed at the correction of cerebral edema and immunological disturbances is substantiated. In particular, the indications for the administration of intravenous immunoglobulin for immunoglobulin replacement purposes and dexamethasone for anti-inflammatory purposes in children with bacterial purulent meningitis and pronounced cerebral edema are scientifically substantiated. The results of the work have been implemented in the practice of the children's infectious clinical hospital and are used in the educational process of the medical university.

According to data from the World Health Organization (WHO) [210, 250, 364, 369], approximately 1 million cases of bacterial purulent meningitis (BPM) are registered worldwide annually, of which 200 thousand cases are fatal. Within the structure of general pathology of the nervous system, meningitis is one of the most frequent clinical forms [18, 26, 182, 263]. The incidence of meningitis among children in the Russian Federation averages 8.22 per 100,000 population annually [47, 213, 224, 255]. The overwhelming majority (80%) are children under the age of five [213, 293, 348]. High mortality persists in purulent meningitis, averaging 4–10%, which is attributable to the severity of the disease course and its numerous complications. These include: infectious-toxic shock (ITS), hypertensive-hydrocephalic syndrome (HHS), neurosensory hearing loss syndrome, development of pareses and paralyses, and apallic syndrome. Persistent organic lesions of the central nervous system (CNS) in the residual period are observed in nearly one-third of recovered children [68, 78, 81]. The causative agents of BPM may be virtually any microorganisms that have entered the meninges and cerebrospinal fluid (CSF); however, the leading role in the etiology of the disease continues to belong to Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b, and less frequently to Streptococcus, Staphylococcus, and other conditionally pathogenic bacteria (CPB). An unfavorable clinical outcome is attributable both to the physiological immaturity of the immune system in young children and to the insufficient study of the specific features of BPM pathogenesis, as well as the absence of reliable criteria for determining the severity of the disease process and for evaluating the adequacy of the treatment administered [11, 112, 185, 213, 224, 255, 263]. The disease outcome and the severity of clinical manifestations depend largely on the response of the host's metabolic systems to infectious stress and on the ability of the humoral and phagocytic components of the immune system to adequately respond to the pathogen. However, the available literature contains limited information on the changes occurring [213], and the metabolic processes and immunological changes taking place in the CSF of patients with bacterial purulent meningitis have been almost entirely unstudied. In this regard, the study of metabolic processes and immune status indicators at the systemic (blood) and organ (CSF) levels in relation to the intensity of inflammatory reactions and the severity of BPM in children represents a matter of scientific and practical interest. It is quite likely that resolving these issues will contribute to improving the diagnosis and prognosis of the disease, optimizing pathogenetic therapy, and reducing mortality in bacterial purulent meningitis in children. The aim of the study: based on the study of the clinical features and individual links of pathogenesis of bacterial purulent meningitis in children, to substantiate pathogenetic therapy aimed at the correction of cerebral edema and immunological disturbances. The objectives of the study: 1. To analyze the prevalence and etiological structure of bacterial purulent meningitis in children in the Khabarovsk Territory based on materials from the children's infectious hospital of Khabarovsk. 2. To study the clinical manifestations of bacterial purulent meningitis in children depending on the severity of cerebral edema. To establish diagnostic criteria for stages of cerebral edema using clinical, instrumental (reoencephalography, electroencephalography), and laboratory methods. 3. To provide a pathogenetic assessment of metabolic disturbances in brain tissues in patients with bacterial purulent meningitis depending on the magnitude of cerebral edema. 4. To establish the patterns of changes in phagocytic defense and major components of immunity (cellular and humoral) depending on the stage of cerebral edema in children with bacterial purulent meningitis. 5. To substantiate the use of additional methods of pathogenetic therapy to prevent the progression of cerebral edema and to improve the prognosis and outcomes of the disease in children. The scientific novelty of the research: 1. The etiology and epidemiology of BPM in children in the Khabarovsk Territory were studied for the first time, including a description of mixed-etiology BPM. 2. Clinical, instrumental, and laboratory criteria for the comprehensive diagnosis of cerebral edema in children with BPM were developed. 3. Clinical and laboratory indications for the administration of intravenous immunoglobulin (IVIG) for immunoglobulin replacement purposes and dexamethasone for anti-inflammatory purposes in children with BPM were developed and scientifically substantiated. The practical significance of the work: 1. The determination of a point-based assessment of clinical symptoms using instrumental research methods — REG and EEG — allows for the precise determination of the stage of cerebral edema in children with BPM. 2. The determination of the cytokine status is recommended for use as a comprehensive indicator of the level of the inflammatory reaction in brain tissue in children with BPM and the stage of cerebral edema. 3. The determination of lactate content and neuron-specific proteins — neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) — in the blood and CSF of children with BPM constitutes an objective indicator of the severity of CNS damage and the prognosis of the disease course. 4. The detection of phagocytic, cellular, and humoral immune deficiency in children with BPM and cerebral edema of stage III constitutes a basis for the prescription of immunoglobulin replacement therapy. 5. The administration of IVIG and dexamethasone in patients with BPM and pronounced cerebral edema contributes to a reduction in the frequency of specific complications and a shortening of the duration of hospitalization. Implementation in practice: 1. The research results are used in the practical work of physicians at the MUZ «Children's Infectious Clinical Hospital» named after A.K. Pirogovich. The obtained data are used in the educational process at the GOOU DPO «Institute of Advanced Training of Healthcare Specialists» of the Ministry of Health of the Khabarovsk Territory and at the GOOU VPO «Far Eastern State Medical University» of the Ministry of Health and Social Development of Russia. 2. A teaching-methodological manual for instructors titled «Bacterial Purulent Meningitis in Children» has been developed and implemented with the endorsement of the UMO, 2009. 3. A monograph titled «Bacterial Purulent Meningitis in Children», Khabarovsk, 2011, 159 pp., has been published. 4. Five rationalization proposals based on the research results have been prepared (2007, 2009, 2010, 2011, 2012). 5. Based on the dissertation results, 38 printed works have been published, including 18 in peer-reviewed journals recommended by the VAK of the Ministry of Education and Science of Russia. 6. Based on the conducted research, two priority certificates for inventions have been obtained — No. 2012102634 dated 25.01.12 and No. 2012102295 dated 23.01.12. Validation of the dissertation materials: The dissertation materials were presented at: the Jubilee All-Russian Scientific and Practical Conference «Actual Issues of Mixed Infections» (St. Petersburg, 9–11 October 2007); the VIII International Congress «Evidence-Based Medicine — the Foundation of Modern Healthcare» (Khabarovsk, 18–20 October 2008); the Scientific and Practical Conference «Neuroinfections of the Far East» (Khabarovsk, 25 December 2009); the III Regional Scientific and Practical Conference with International Participation «Actual Issues of Infectious Pathology in the Far East» (Khabarovsk, 26–28 May 2008); the Scientific and Practical Conference dedicated to the anniversary of the Khabarovsk Scientific Research Institute of Epidemiology and Microbiology (Khabarovsk, 7 October 2010); the All-Russian Congress «Infectious Diseases in Children: Diagnosis, Treatment, and Prevention» (St. Petersburg, 5–6 October 2010); the Far Eastern Regional Scientific and Practical Conference «Actual Problems of Pediatrics» (Khabarovsk, 16 September 2011); the 10th International Congress «Evidence-Based Medicine — the Foundation of Modern Healthcare» (Khabarovsk, 26–30 September 2011); the X Congress of Russian Pediatric Infectious Disease Specialists «Actual Issues of Infectious Pathology and Vaccination Prevention» (Moscow, 3–6 December 2011); the session of the Khabarovsk Territorial Society of Epidemiologists and Infectiousists (8 October 2009). Structure and scope of the dissertation: The work consists of an introduction, a literature review, a chapter titled «Materials and Methods of Research», four chapters of original research, a conclusion, conclusions, and practical recommendations. The dissertation is presented on 287 pages of typed text, illustrated with 51 tables and 7 figures. The bibliography includes 405 sources, of which 257 are Russian and 148 are foreign.