Meningococcal infection: clinical guidelines

List of Abbreviations

MI — meningococcal infection

MNP — meningococcal nasopharyngitis

GMI — generalized form of meningococcal infection

Mc — meningococcus

MM — meningococcal meningitis

MC — meningococcemia

ESR — erythrocyte sedimentation rate

BLB — blood-liquor barrier

ITS — infectious-toxic shock

DIC – disseminated intravascular coagulation

SIRS — systemic inflammatory response syndrome

MODS - multiple organ dysfunction syndrome

Cerebral edema — cerebral edema and swelling

ARF — acute renal failure

ICU - intensive care unit

LPS — lipopolysaccharide (endotoxin)

EAA — endotoxin activity assay 

D-dimer — fibrin D-dimer

CNS - central nervous system

CBV – circulating blood volume

CVP — central venous pressure

BP — blood pressure

HR – heart rate

LLA — latex agglutination assay

IMV — mechanical ventilation (artificial lung ventilation)

DNA - deoxyribonucleic acid

CT — computed tomography

MRI — magnetic resonance imaging

PCR — polymerase chain reaction

ARVI — acute respiratory viral infections

EMS — emergency medical services

AMT — antimicrobial therapy

RRT — renal replacement therapy (according to medical services nomenclature: Hemodialysis, Blood hemofiltration)

EBC — extracorporeal blood correction (according to medical services nomenclature: Hemosorption, Selective lipopolysaccharide hemosorption, Hemodialysis with selective plasma filtration and adsorption)

ICD-10 — International Statistical Classification of Diseases and Related Health Problems 10th Revision

Terms and Definitions

Meningococcal infection is an infectious disease caused by Neisseria meningitidis.

Meningococcal carriage is the carriage of meningococci on the nasopharyngeal mucosa without impaired health status.

Meningococcal nasopharyngitis is a localized form of meningococcal infection characterized by inflammation of the nasopharynx.

Generalized meningococcal infection is a meningococcal infection accompanied by bacteremia, intoxication syndrome, and predominantly lesions of the meninges and/or blood vessels.

Meningococcemia is a generalized form of meningococcal infection accompanied by marked intoxication, hemorrhagic rash, and the possible development of complications such as ITS.

Meningitis is a generalized form of meningococcal infection accompanied by marked intoxication, purulent lesions of the meninges, and the possible development of cerebral edema.

Combined form of meningococcal infection is a combination of the clinical presentation of different forms of meningococcal infection (meningitis, meningococcemia).

Lumbar puncture — spinal puncture, introduction of a needle into the subarachnoid space of the spinal cord at the lumbar level to obtain CSF.

Cerebrospinal fluid (CSF, liquor) is a fluid constantly circulating in the cerebral ventricles, CSF pathways, subarachnoid space of the brain and spinal cord, protecting the brain and spinal cord from mechanical impacts and maintaining constant intracranial pressure; intracranial pressure performs neurotrophic, resorptive, and transport functions, among others.

Endotoxin (lipopolysaccharide, LPS) is a component of the outer membrane of gram-negative bacteria, a macromolecule consisting of a polysaccharide linked to a lipid, which, upon entering the body and binding to cellular receptors, causes inflammation and septic shock.

Endotoxin activity assay (EAA) is a method for assessing the concentration of endotoxin in the blood. The endotoxin activity assay is used for the early identification of patients at high risk of severe sepsis and septic shock, as well as for evaluating treatment efficacy.

Meningococcal serogroup — strains causing MI are classified according to the chemical composition of their polysaccharide capsule, which has a complex antigenic structure.

Blood-liquor barrier is a histohematic barrier between the bloodstream and the CSF located in the subarachnoid space, represented by epithelial cells with tight junctions lining the choroid plexus of the brain ventricles.

Blood-brain barrier is a histohematic barrier between the bloodstream and the brain parenchyma, represented by the vascular wall of the microvasculature of the brain.

Severity of a disease or condition is a criterion determining the degree of damage to human organs and/or body systems or impairment of their functions caused by the disease, condition, or their complications. Organ or multiple organ failure is the main criterion for transfer to the ICU.

Systemic inflammatory response syndrome (SIRS) is a medical term denoting the general inflammatory response of the body to the invasion and generalization of an infection, regardless of the localization of the focus. The process proceeds with the participation of inflammatory mediators involving virtually all body systems. This reaction is an adaptive function of the body aimed at destroying the causative agent and restoring damaged tissue.

Infectious-toxic shock (Gram-negative septic shock) is a type of shock caused by the damaging effect of meningococcal endotoxin on blood vessels, endothelial damage, activation of cascade systems (coagulation, complement, kallikrein-kinin), leading to a systemic inflammatory response, severe hemodynamic disorders, microcirculation and tissue blood supply impairments, and the development of multiple organ dysfunction syndrome.

DIC syndrome is a syndrome of disseminated intravascular coagulation leading to impaired microcirculation and tissue perfusion, consumption of clotting factors, and the development of hemorrhagic syndrome.

Brain swelling-edema – a pathological inflammatory process characterized by excessive fluid accumulation in the cells of the brain or spinal cord (primarily glia) and the intercellular space, increased brain volume, and intracranial hypertension, which causes brain dislocation shifts, severe hemodynamic and respiratory disorders.

Renal replacement therapy – a set of specialized methods for replacing kidney function. Methods include prolonged hemofiltration and hemodialysis, intermittent hemodialysis, and peritoneal dialysis. All techniques are based on the exchange of dissolved substances and the removal of fluid and pathological products from the blood (specifically endotoxins) using dialysis and filtration through water-permeable membranes.

Extracorporeal blood correction methods (EBC) – a group of modern therapeutic methods in which various components of the patient's blood (plasma, etc.) are processed to eliminate pathologies that cause and sustain a disease. A variant – cascade plasma filtration, a high-tech semi-selective method that allows for the selective removal of pathogenic substances (endotoxins), bacteria, and viruses from blood plasma while preserving beneficial elements. It is one of the most effective modern extracorporeal blood "cleansing" methods used worldwide. They are recommended not only for organ function replacement but also to reduce the severity of systemic inflammatory response syndrome (SIRS).

Evidence-based medicine – an approach to medical practice in which decisions regarding the use of prophylactic, diagnostic, and therapeutic interventions are made based on scientific evidence of their efficacy and safety. Evidence is evaluated, compared, summarized, and widely disseminated for use in the best interests of patients. Decisions on the use of prophylactic, diagnostic, and therapeutic measures are made based on available evidence, their efficacy, and safety.

Disease – a pathological state caused by the impact of pathogenic factors, manifested by impaired bodily functions accompanied by the simultaneous development of the body's protective and adaptive reactions.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnosis, treatment, and rehabilitation methods in providing medical care, and the degree of achievement of the planned result.

Clinical guidelines are documents based on proven clinical experience that describe a physician's actions regarding the diagnosis, treatment, rehabilitation, and prevention of diseases, helping them make correct clinical decisions.

Level of evidence certainty – reflects the degree of certainty that the cited fact of a medical intervention is true.

Level of recommendation certainty – reflects not only the degree of confidence in the validity of the intervention's effect, but also the degree of confidence that following the recommendations will bring more benefit than harm in a specific situation.

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

Laboratory diagnostics – a set of various research methods involving biological material using specialized laboratory equipment.

SOFA scale (Sequential Organ Failure Assessment) – a dynamic assessment of organ failure and dysfunction.

Glasgow Coma Scale (GCS) – a scale for assessing impaired consciousness and coma.

Medical intervention – actions (prophylactic, diagnostic, therapeutic, rehabilitative, research) performed by a medical professional authorized to carry out medical activities.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Meningococcal infection [Greek *meninx*, *meningos* – membrane, *kokkos* – grain, seed] – an acute anthroponotic infectious disease transmitted via airborne droplets (Neisseria meningitidis), manifested by intoxication, damage to the nasopharyngeal mucosa, and possible generalization in the form of specific septicemia and/or purulent meningitis with characteristic changes in the cerebrospinal fluid, the appearance of a characteristic hemorrhagic rash, and, less frequently, damage to other organs and systems [1, 2, 3, 4, 24, 28, 57, 64].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causative agent of meningococcal infection, Neisseria meningitidis, is a Gram-negative, non-motile diplococcus belonging to the genus Neisseria, family Neisseriaceae. Typically, they are located in pairs inside neutrophils. Based on their antigenic structure and the characteristics of their polysaccharide capsule, meningococci are divided into 12 serogroups: A, B, C, H, I, K, L, X, Y, Z, W, E29. The vast majority of cases worldwide are caused by six serogroups: A, B, C, Y, X, and W; the rest are detected in isolated cases. In turn, N. meningitidis of each serogroup is subdivided into subgroups differing in genetic characteristics. The proportion of serogroup W meningococcus has been steadily increasing in recent years; some group W strains belonging to sequence type ST-11 (clonal complex cc11) possess hypervirulent properties, and the disease is characterized by a severe course with atypical manifestations (pneumonia, endocarditis, fasciitis, epiglottitis) and high mortality up to 30 - 57% [5, 6, 7, 8, 9, 11, 13, 18, 19, 23, 24]. Meningococcal pathogenicity factors include the capsule, which prevents complement-mediated bacterial lysis and phagocytosis; pili, responsible for adhesion (attachment) to the surface of nasopharyngeal epithelial cells; surface proteins, in particular factor H-binding protein (fHBP), which inhibit complement system activation; IgA proteases; and lipopolysaccharide (LPS) (endotoxin), which is considered the main pathogenicity factor of meningococci and surpasses the LPS of other Gram-negative bacteria in its toxic properties due to a high polyunsaturated fatty acid content. In cerebrospinal fluid and blood smears, meningococci are located predominantly intracellularly in the cytoplasm of polymorphonuclear neutrophils, and less frequently, in fulminant forms during the first hours of the disease, extracellularly. Meningococcus is unstable in the environment, dying upon drying and exposure to direct sunlight, temperatures below 22°C, and disinfectants. It is cultivated under aerobic conditions on media containing protein or a set of amino acids. The course of the infectious process is determined by the characteristics of the pathogen, infection conditions, and immunogenetic factors. Meningococcus has a dual nature. On the one hand, it is a pyogenic coccus causing purulent meningitis; on the other hand, it contains LPS, which determines the development of intoxication syndrome. Defense mechanisms in MI depend on the barrier functions of the nasopharyngeal epithelium, the action of secretory IgA, the complement system, the phagocytic activity of polymorphonuclear neutrophils, and specific bactericidal antibodies. Meningococci colonize the human nasopharynx, causing asymptomatic carriage lasting from a week to a year, which is accompanied by the development of specific immunity, preventing the likelihood of developing generalized forms of the disease. A preceding respiratory infection, especially influenza, promotes the generalization of MI. Meningococcal carriage is not accompanied by health disorders, but nasopharyngeal examination in most cases reveals a picture of acute follicular pharyngitis. Generalization of the infection is promoted by: high IgA protease activity of the strain, and a high infecting dose during close contact. Antibacterial defense systems in the mucous membrane and blood in most cases prevent the generalization of the infection and lead to the elimination of meningococcus. In the first months of life, maternal specific IgG is present in the blood; the level of own antimeningococcal antibodies usually increases with age, so at least 50% of patients are children under five years of age.

A significant role in defense against meningococcal infection is played by genetic predisposition; specifically, in individuals with congenital deficiencies of terminal complement components (C5, C6, C7, C8), component C3, or properdin, generalized meningococcal infection (GMI) occurs 1,000 to 5,000 times more frequently than in individuals with a normal complement system [2, 3, 4, 10]. Individuals with terminal complement component deficiency (TCCD) may experience recurrent episodes of GMI, on average every 10 to 20 years, although a severe and complicated course of the infection is not typical. Increased incidence of meningococcal infection, and in some cases a more severe course of GMI, have also been identified in individuals with a genetically predetermined elevated concentration of factor H, individuals with reduced functional activity of mannose-binding lectin (which is involved in meningococcal opsonization and complement activation), individuals with a non-functional variant of the Toll-like receptor 2 or 4 gene (one of the endotoxin receptors and an element of the innate immune response to gram-negative bacteria), macrophages, and individuals with reduced phagocytic capacity due to a less effective FcγRIIa (CD32) receptor allele on neutrophils. The most critical link in the pathogenesis of GMI is bacteremia. In this case, the course of the infectious process depends on the balance between the pathogenic properties of the causative agent and the host defense mechanisms. In mild meningococcal infection with a low level of endotoxin (lipopolysaccharide, LPS), activation of inflammation, the complement system, and phagocytosis occurs, leading to rapid elimination of the pathogen. With a higher level of bacteremia and toxinemia, complement consumption occurs, phagocytosis is suppressed, the bactericidal activity of the blood decreases, and pathogen multiplication in the blood is observed alongside a significant increase in LPS levels, suppression of phagocytosis, and platelet activity.

In mild forms of meningococcal infection, the death of the meningococcus is accompanied by the release of small amounts of LPS, which exhibit an activating effect on the body's defense systems: fever appears, neutrophil release into the blood and their phagocytic activity are stimulated, the complement system is activated, blood bactericidal activity increases, and the body rapidly clears the pathogen. With a higher level of bacteremia and toxinemia, complement consumption occurs, phagocytosis is suppressed, blood bactericidal activity decreases, and pathogen multiplication in the blood is observed along with the accumulation of high doses of LPS, which suppress not only phagocytosis but also the functional activity of platelets.

A high correlation has been found between the concentration of LPS in the patient's blood and the severity of the disease: septic shock develops at an LPS blood concentration exceeding 800–1000 ng/µL, and at an LPS concentration above 8000 ng/µL, shock is generally irreversible. Endotoxemia leads to the activation of major biochemical blood systems, particularly the coagulation system, which can be followed by its exhaustion, contributing to the development of a typical meningococcal rash and, in severe cases, disseminated intravascular coagulation (DIC) syndrome. Endotoxin is released not only upon the death of meningococci but also during their multiplication in the blood. LPS activates macrophages and neutrophils, leading to the activation of inflammation, increased bactericidal activity, and cell migration to the site of infection to ensure phagocytosis. In meningococcal infection complicated by septic shock, hyperactivation of blood cells has a pronounced pathological effect [2, 8, 9, 10, 11]. Unregulated release of massive amounts of biologically active substances (kinins, catecholamines, interleukins) initiating a systemic inflammatory response is clinically manifested by the development of septic shock. Vascular wall damage, disruption of macro- and microcirculation, and septic shock are accompanied by tissue and organ damage, leading to the development of renal, pulmonary, and cardiac failure, as well as brain swelling and edema. Central hemodynamic disturbances occur later. This explains the rapid progression and high mortality rate of fulminant meningococcal infection.

The course of the infectious process depends on the ratio of the pathogen's virulence factors to host defense mechanisms. Under conditions of intensive bacteremia, neutrophils rapidly deplete their myeloperoxidase reserve, leading to incomplete phagocytosis. Neutrophils containing viable meningococci serve as a transport system for the pathogen across intact blood-tissue barriers into the subarachnoid space or joint cavities, where purulent inflammation develops. The penetration of the pathogen into the subarachnoid space leads to the development of purulent meningitis. The earliest signs to be detected are increased blood-brain barrier permeability and CSF production, which is accompanied by elevated CSF pressure and an increase in CSF glucose concentration to 3–4 mmol/L or more; prior to the appearance of inflammatory changes, lactate levels rise to 5–15 mmol/L and pH drops below 7.20 [2, 4, 12]. Cell counts and protein levels may remain within normal limits, but the pathogen can be detected by microscopic examination of cerebrospinal fluid for meningococci (Neisseria meningitidis) extracellularly, molecular genetic testing of blood for meningococci (Neisseria meningitidis) (PCR), and isolation of the meningococcal culture via bacteriological (cultural) examination of cerebrospinal fluid for meningococci (Neisseria meningitidis). Subsequently, within a few hours, the clinical picture of diffuse purulent meningitis develops with an increase in neutrophilic pleocytosis to 4–5-digit levels, elevated protein and lactate levels, and decreased glucose levels. The severity of the course and outcome of meningitis in the early stages is determined by the severity of acute brain swelling and edema (ABSE), and in later stages in the absence of adequate therapy, by the involvement of the brain parenchyma and ventricles in the process. Three components play a leading role in the pathogenesis of ABSE: cytotoxic, inflammatory, and ischemic (due to impaired hemodynamics and CSF dynamics). Overall, more than 90% of deaths from meningococcal meningitis are caused by ABSE. About 10% of deaths are caused by progressive meningoencephalitis. Post-infection immunity in generalized forms is quite robust, and reinfections and relapses are rare. Polysaccharide vaccines for the prevention of meningococcal infection (ATX code: J07AH, bacterial vaccines) elicit a fairly strong immune response and provide protection for at least 3 years; their epidemiological efficacy reaches 85–95% [2, 3, 5, 9, 14, 17, 18].

1.3 Epidemiology of the Disease or Condition

Meningococcal infection (MI) is ubiquitous. N. meningitidis can cause both endemic and epidemic outbreaks affecting all age groups in the population. The circulation of meningococci in the form of asymptomatic carriage, serogroup variability of the pathogen (the emergence of hypervirulent strains), and population migration form the basis for the periodic activation of the epidemic process of MI. Currently, the epidemic process of MI is characterized by the alternation of seasonal periods of incidence increase and decrease (by months of the year) and periods of increased incidence interspersed with periods of epidemiological well-being every 10–15 years. Meningococci of serogroups A, B, C, W, and X are most frequently the cause of cases, outbreaks, and epidemics. During periods of sporadic incidence, serogroup B meningococcus is predominantly detected. Since the 1980s, the Russian Federation has experienced relative epidemiological well-being, with MI being registered as sporadic incidence. Starting in 2018, an increase in MI incidence was observed, with the incidence rate rising by 15.5% compared to 2016; however, this trend was interrupted by the COVID-19 pandemic in 2020–2022 thanks to mass individual prevention measures, causing the MI incidence rate to drop to 0.26 per 100,000 population in adults. An increase in the number of MI cases began to be observed again from 2022 onwards, largely due to the lifting of COVID-19 restrictive measures. The tense epidemiological situation manifests as the largest increase in MI incidence in large metropolitan areas (Moscow, St. Petersburg) and among organized population groups.

The average long-term incidence rate of generalized meningococcal infection (GMI) in the Russian Federation (RF) for the period 2014–2024 was 0.45 per 100,000 population. The incidence rate shows no statistically significant decrease, remaining at 0.42 in 2023 and 0.47 in 2024. The nationwide rate has decreased by a factor of 1.3 over 11 years. The most vulnerable federal district (FD) was the Central Federal District, where this rate reached 0.7 per 100,000 population, which is 1.5 times higher than the corresponding figure for the RF as a whole. Among the 18 regions of the Central Federal District, the highest average long-term incidence rate was recorded in Moscow at 1.3 per 100,000 population (2.8 times higher than the overall RF figure); among children for the period 2024–2024, this rate was 1.5 per 100,000 child population, which is 3 times higher than the national average. A statistically significant downward trend in GMI incidence rates among children aged 0–14 years has been identified. Over the past period, the incidence among children decreased by 2.3 times [15–18]. The average long-term incidence rate among children in the RF for 2014–2024 exceeded that of adults by 7.5 times. In recent years (2023 and 2024), the gap between adult and childhood incidence rates has narrowed thanks to vaccination. In 2024, the childhood incidence rate exceeded the adult rate by 3 times (the analysis is based on official statistics: Federal Statistical Monitoring. Data on infectious and parasitic diseases for 2014–2024, Form 2).

It is generally accepted that the incidence of MI is seasonal, manifesting primarily during the winter-spring period. However, a monthly analysis over the past 5 years shows that currently there is no clear seasonal clustering of MI cases, and they are diagnosed throughout the entire year [5, 12, 13, 18].

In accordance with the provisions of Order of the Russian Ministry of Health No. 375 dated December 23, 1998, "On measures to strengthen epidemiological surveillance and prevention of meningococcal infection and purulent bacterial meningitis," as well as in accordance with Methodological Guidelines MUK 4.2.4067-24 (4.2. Control Methods. Biological and microbiological factors. Laboratory diagnostics of meningococcal infection and purulent bacterial meningitis. Guidelines for control methods, microbiological (cultural) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), and microbiological (cultural) blood sterility testing), biological samples from every patient diagnosed with "meningococcal infection" must be subjected to laboratory confirmation and study of the biological properties of strains isolated from patients. Data on the efficacy of laboratory testing in 2024 showed that the percentage of bacteriological laboratory confirmation for the diagnosis of "meningococcal infection" was 57.0%, isolation of genetic material via molecular biological examination of cerebrospinal fluid/blood for meningococcus (Neisseria meningitidis) (PCR) was 83%, and 67.5% of cases were serotyped (compared to 61.6% in 2023) [4, 6, 12].

Modern manifestations of the MI epidemic process are characterized by continuous changes in the serogroup characteristics of meningococcal strains; over the past 10 years in the Russian Federation, instability of the dominant meningococcal serogroup has been observed. Out of the 12 meningococcal serogroups, the most common ones circulating in Russia in recent years are A, B, C, and W. Since 2010, serogroup W meningococcus has spread globally in the RF, accounting for up to 34–56% of cases in large metropolitan areas, whereas its incidence previously did not exceed 1% [4, 5, 6, 13, 17, 19–24]. From 2020 to 2025, variability in the dominant meningococcal serogroup has also been observed: there was an increase in N. meningitidis A (averaging 59.7%), while maintaining a high proportion of N. meningitidis W (32.9%), a decrease in the proportion of N. meningitidis B (averaging 3.1%), and a consistently low level of N. meningitidis C (5.3%); the proportion of other (rare) serogroups has not exceeded 2% over the past 15 years [2, 3, 17, 19, 24].

The source of the infectious agent is patients with various forms of meningococcal infection (MI) and meningococcus carriers. Carriers and patients with meningococcal nasopharyngitis pose the greatest danger. There are up to 2,000 carriers per patient with a manifest form of MI, with a carrier rate of 4–15% in the general population, which can reach 50% of the population in an infection focus during an epidemic. The average duration of meningococcal carriage is 2–3 weeks, and in 2–3% of individuals, it may persist for up to 6 weeks or more [1, 3, 6, 8]. Transmission most commonly occurs from asymptomatic carriers and less frequently through direct contact with patients with invasive meningococcal disease (IMD). Acute nasopharyngitis develops in 10–20% of the total number of infected individuals. In a small proportion of infected individuals—about 1–2%—a generalized form of the disease is observed: meningococcemia, meningitis, or a combined form (meningitis + meningococcemia).

The transmission mechanism is aerosol, and the route is airborne. Due to the extreme fragility of meningococcus outside the human body, transmission is facilitated by crowding (70% of transmissions occur at a distance of less than 0.5 m), close contact (schools, kindergartens, dormitories, hostels, hotels, barracks, boarding schools, etc.), high ambient temperature and humidity, and poor living sanitation and hygiene standards. The contagiosity index is 10–15%. Prior impairment of the body's condition (stress reactions, acute respiratory viral infections, sudden climate changes, vaccinations, trauma, etc.) is of significant importance.

Immunity is type-specific; recurrent infections are caused by different serological types of the pathogen. Population immunity is formed as a result of carriage or meningococcal nasopharyngitis. Infants in the first months of life may have congenital passive immunity acquired from the mother, while their own immunity to MI is typically formed by the age of 5, making this age group the most susceptible to the disease. IMD is more common in urban populations than in rural areas [1, 2, 3, 6, 7, 8, 9, 10, 13, 17, 24].

Susceptibility to meningococcus is universal and depends on the presence of prior specific immunity in the individual, which is acquired mainly through repeated contact with the pathogen and the development of carriage or meningococcal nasopharyngitis [1, 3, 7, 8, 9, 10, 18, 19, 21].

In the Russian Federation, a Reference Center for Monitoring Meningococcal Infection has been established at the Central Research Institute of Epidemiology of Rospotrebnadzor, whose regulatory acts make a significant contribution to improving the quality and effectiveness of epidemiological surveillance of meningococcal infection [17]. Globally, the relevance of this issue is confirmed by the establishment of The Global Meningococcal Initiative (GMI) [11].

1.4 Features of Coding the Disease or Condition

Forms of generalized MI are included in category A "Certain infectious and parasitic diseases":

A39 Meningococcal infection

A39.0 Meningococcal meningitis (G01*)

A39.1 Waterhouse-Friderichsen syndrome (E35.1*)

A39.2 Acute meningococcemia

A39.3 Chronic meningococcemia

A39.4 Meningococcemia, unspecified

A39.5 Meningococcal heart disease

A39.8 Other meningococcal infections

A39.9 Meningococcal infection, unspecified

1.5 Classification of the disease or condition

According to the classification by V.I. Pokrovsky, accepted in the Russian Federation, localized (meningococcal nasopharyngitis) and generalized forms of the disease (IMD) are distinguished [1, 2, 3, 4]:

I. Localized forms:

• meningococcal carriage

• acute nasopharyngitis

According to ICD-10, meningococcal infection and meningococcal carriage are included in category Z "Factors influencing health status and contact with health services" — Z22.3 – Carrier of meningococcal infection.

II. Generalized forms:

• meningococcemia

• meningitis

III. Combined form — a combination of meningitis and meningococcemia.

IV. Rare forms of meningococcal infection:

• myocarditis (pericarditis, endocarditis)

• pneumonia

• iridocyclitis, conjunctivitis

• arthritis

• encephalitis

• optic neuritis

• meningococcal bacteremia, NOS (not otherwise specified)

By severity:

1. Mild

2. Moderate

3. Severe

4. Fulminant

By clinical course duration:

1. Acute

2. Prolonged

By the nature of the course:

1. Uncomplicated

2. Complicated

3. With secondary infection

4. With exacerbation of chronic diseases

1.6 Clinical presentation of the disease or condition

The incubation period ranges from 2 to 10 days, with an average of 4 days.

Meningococcal nasopharyngitis is the most frequent manifestation of MI. In most cases, it is an independent form of MI, but it can precede IMD (in 30–60% of patients with generalized infection). Patients complain of nasal congestion, scanty nasal discharge, mild cough, and headache. Half of the patients experience a fever lasting from 1 to 4 days, usually low-grade, and up to 38.0–38.5 °C in more severe cases. Examination reveals pallor of the skin, and injection of scleral and conjunctival vessels. The mucous membrane of the anterior oropharynx appears normal, while the posterior pharyngeal wall is hyperemic, edematous, and often covered with mucous exudate. From the 2nd–3rd day, lymphoid follicle hyperplasia appears. Inflammatory changes are particularly pronounced in the nasopharynx, spreading to the posterior part of the choanae and nasal passages, which leads to impaired nasal breathing. After a few days, inflammatory changes subside, but follicle hyperplasia persists for up to 2 weeks. The hemogram in meningococcal nasopharyngitis is largely unremarkable; in more severe cases, neutrophilic leukocytosis with a left shift and an elevated ESR up to 30 mm/h are possible. The clinical picture of nasopharyngitis is non-specific; a definitive diagnosis is established only by microscopic examination of swabs from the posterior pharyngeal wall for meningococcus (Neisseria meningitidis).

Meningococcemia– begins acutely amidst complete health or against the background of nasopharyngitis. Symptoms depend on the severity of the disease. In moderate severity, temperature rises with moderate chills to 38 – 39⁰°C, accompanied by moderate headache, and by the end of the first day or the beginning of the second, a sparse hemorrhagic rash appears. The rash elements do not exceed 0.5 cm in diameter, located predominantly in the distal extremities and buttocks; sometimes primary appearance of a roseolous rash with further metamorphosis into a hemorrhagic one is possible. Moderate tachycardia and arterial hypotension are noted. In severe disease, pronounced chills, body aches, sharp weakness, and temperature with pronounced chills rising to 39 – 40 are noted⁰°C, the rash appears within the first 12 hours of the disease, hemorrhagic, profuse, large up to 1-2 cm in diameter; along with the extremities, rash elements are present on the face and trunk, large elements become necrotic, and conjunctival hemorrhages are frequent. Extremities are cold, cyanosis of the nail phalanges. Pulse is rapid, of poor volume, blood pressure is reduced within up to 50% of the age norm, diuresis is reduced to 200 – 500 mL — i.e., the picture of compensated septic shock. In very severe disease, the onset is abrupt, temperature with shaking chills rises to 40 – 41⁰°C, vomiting and diarrhea are frequently observed, the rash appears in the first hours of the disease, large with hemorrhagic necrosis, predominantly localized on the face and trunk, numerous hemorrhages in the mucous membranes of the eyes and mouth. The picture of septic shock can develop in the first hours of the disease, sometimes before the appearance of the rash. Temperature rapidly drops to normal or subnormal levels. Extremities are cold, acrocyanosis. Blood pressure drops to 50% of the age norm, often unmeasurable, marked tachycardia, shortness of breath, weakened breath sounds on auscultation, especially in the lower parts, oligoanuria. Without adequate therapy, death occurs within 1-2 days. When acute neurogenic meningitis joins, consciousness is impaired, convulsions and respiratory disorders appear. Regardless of severity, serous polyarthritis may develop early on. Acute endocarditis/myocarditis, pneumonia are possible. The blood picture is characteristic: neutrophilic leukocytosis up to 20 - 32 x 10*⁹/L, with a left shift, thrombocytopenia. In very severe cases, leukopenia, a decrease in platelet count below 20 x 10*⁹/L, and a pronounced picture of DIC syndrome are observed. When examining acid-base status and blood gases (ABG) — decompensated metabolic acidosis (pH <7.4), a decrease in O₂levels, and an increase in CO₂levels. Microscopic examination of a blood smear in very severe cases may reveal intra- and extracellular clusters of meningococcus.

Meningitis begins acutely, though not violently. Chills and headache appear, and body temperature reaches 38.5–39.5 °C during the first 24 hours. The headache rapidly intensifies and by the end of the day becomes severe, bursting, and diffuse; it worsens with movement, light, and sound, and is not relieved by analgesics and antipyretics (ATC code: N02B). Nausea follows, then projectile vomiting. Concurrently, skin hyperesthesia develops, which may mimic localized pain typical of acute surgical abdominal or renal diseases. By the end of the 1st day or on the 2nd day of the disease, meningeal signs appear (nuchal rigidity, upper, middle, and lower Brudzinski's signs, and bilateral Kernig's sign). From the 2nd–3rd day of the disease, patients may assume a characteristic "meningeal" posture: lying on their side with the head thrown back and legs drawn up to the torso. Without etiological treatment, general cerebral syndrome develops within 3–5 days: lethargy, stupor, psychomotor agitation. Focal signs may appear, such as cranial nerve palsies (most commonly facial and oculomotor nerves), pyramidal signs, and occasionally limb paresis or pelvic sphincter disorders, indicating the development of complications such as cerebral edema and swelling, as well as various intracranial complications: cerebrospinal fluid circulation disorders, cerebral infarction, cerebritis, etc.

A serious complication is the development of purulent labyrinthitis and cochlear neuritis; tinnitus may occur. No significant pathology is detected in internal organs. Relative bradycardia and an increase in blood pressure, especially systolic, are possible.

During spinal (lumbar) puncture, CSF flows out under elevated pressure from the very first hours of the disease, although hypotension may occur in the presence of frequent vomiting. The earliest CSF change is an increase in lactate level up to 5–20 mmol/L, a drop in pH <7.20, and by day 3, a decrease in glucose, which may become undetectable altogether. Even when the cell count in CSF is still normal, neutrophils appear, and the causative agent can be detected in the cerebrospinal fluid (microscopic examination, microbiological (culture) examination, molecular biological examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis)). Over the next few hours, the CSF becomes purulent and turbid, containing up to 3–10 thousand or more cells per 1 µL (>90% neutrophils), with protein increasing to 1.5–6 g/L or more. Sediment tests become sharply positive. Blood picture in meningitis: leukocytosis is less pronounced than in meningococcemia, within 15.0–20.0×10⁹/L. Urine tests are unremarkable. The most frequent complication of meningitis is acute brain swelling (ABS). Some degree of brain edema is inherent to every case of meningitis. Severe, life-threatening ABS with a herniation syndrome and brainstem compression is observed in 10–20% of patients with invasive meningococcal disease (IMD). ABS can develop anywhere from the first hours of the disease (fulminant form of meningitis), when purulent exudate has not yet formed in the meninges, up to the 3rd–5th day of treatment, particularly in patients older than 70 years with initially reduced cerebral blood flow. Symptoms of severe progressive ABS: confusion, psychomotor agitation rapidly progressing to coma, appearance of generalized clonic-tonic seizures, respiratory disorders: shallow breathing, tachypnea, arrhythmia with increasing hypoxemia and hypocapnia, followed by hypercapnia. Systolic blood pressure is elevated to 140–180 mm Hg, unstable.

The combined (mixed) form of meningococcal infection (meningitis + meningococcemia) is the most frequent [2, 11, 12, 13, 21, 22, 23].

Combined form (meningitis + meningococcemia) — the disease begins with pronounced symptoms of intoxication (temperature of 39⁰ C and above) and the appearance of a meningococcal rash. By the end of the 1st day or on the 2nd day of the disease, often against the background of a secondary rise in body temperature, intense headache, vomiting, and meningeal syndrome appear. The combined form of meningococcal infection can be complicated by infectious-toxic shock (ITS) or ABS, as well as a combination thereof [1, 2, 4, 8, 9, 11, 19, 20, 21, 24].

The main syndromes occurring in various forms of IMD in adults are presented in Appendix A3.1.

The severity of the patient's condition is determined based on the assessment and comparison of clinical and laboratory parameters.

Mild course is characterized by a satisfactory condition of the patient, incidentally detected meningococcal carriage or clinical manifestations of nasopharyngitis, no changes in the complete blood count, and a rapid effect of the therapy administered.

Moderate course is observed against the background of pronounced fever and intoxication.

In meningococcemia, it is characterized by sparse elements of hemorrhagic rash and the absence of signs of cardiovascular system damage.

In meningitis, the presence of meningeal symptoms is characteristic in the absence of general cerebral and focal symptoms.

Severe course — in meningococcemia, high fever and pronounced intoxication are observed; the rash appears early on the first day of the disease, large, increasing in size, abundant, often with a necrotic component, rapidly spreading over the entire body surface; drop in blood pressure, tachycardia, oliguria.

In severe meningitis, in addition to pronounced intoxication and meningeal symptoms, general cerebral symptoms (stupor, sopor, agitation, seizures) and focal symptoms join in, indicating the development of ABS or involvement of the brain parenchyma in the process.

In the very severe (fulminant) course of meningococcemia, hyperthermia is observed, rapidly replaced by hypothermia, the appearance of a rash predominantly localized on the trunk and face, with a large number of necroses in the first hours, early development of hemodynamic disturbance signs: sharp drop in blood pressure, microcirculatory disorders, DIC syndrome, oligoanuria, leukopenia, pronounced thrombocytopenia, decompensated metabolic acidosis, multiple organ dysfunction syndrome.

Meningococcal bacteremia, unspecified (NOS), has a severe course that develops rapidly, with a pronounced intoxication syndrome, without clinical manifestations of skin or meningeal involvement, and proceeds immediately with the progression of ITS symptoms.

Risk factors for a severe course of the disease include the patient's age, genetic factors, as well as late diagnosis of meningococcal infection, underestimation of severity, lack of etiological treatment at the pre-hospital stage, and hospitalization in a non-specialized hospital [4, 5, 12, 13, 19, 20, 23, 24]. Criteria for the severity of the condition are the development of complications: non-specific ones, which can develop in all forms of invasive meningococcal infection (bacterial pneumonia, herpetic infection (herpes labialis)), and specific ones, which correspond to the form of the disease and may also be combined (ABS, ventriculitis, ITS, MODS) [1, 11, 12, 21, 24, 25]. Appendix A3.2.

1.6.1. Clinical criteria for disease severity in meningococcal meningitis (complications)

In the very severe course of meningitis, an increase in general cerebral symptoms (coma), the appearance of focal symptoms, seizures, and respiratory disorders are characteristic, caused by an early complication — ABS with herniation [1, 2, 3, 11, 12, 21, 24, 36, 50, 82, 113]. Severity assessment depends on the patient's level of consciousness; the Glasgow Coma Scale is most frequently used, which is the sum of scores for three parameters — eye opening, verbal response, and motor response. The assessment according to the Glasgow Coma Scale (Appendix G1) correlates with the severity of cerebral injury and the prognosis of the disease and is an important criterion for assessing the level of consciousness. Each individual response is scored in points, and the level of consciousness is expressed as the sum of points for each parameter. The lowest score is 3 points, and the highest is 15 points. A score of 8 points and below is defined as coma. A scale score of 3–5 points is prognostically extremely unfavorable, especially if combined with wide pupils and the absence of the oculo-vestibular reflex. Late complications include neurological sequelae: hearing loss, dizziness, seizures (Appendix A3.2).

1.6.2. Clinical criteria for the severity of meningococcal infection and meningococcemia (complications)

In most cases, all symptoms characteristic of meningococcemia progress, and in the absence of diagnosis and adequate treatment, early and late complications develop. Early complications (in the 1st week of the disease) are specific (infectious-toxic (septic) shock). The symptoms of ITS can develop within 1–3 hours (fulminant form), and in the absence of emergency therapy, death may occur 20–48 hours from the onset of the disease or 5–20 hours from the appearance of the rash. Mortality reaches 70%. Late complications include deep necrosis of distal extremities, dry gangrene, and amputation (Appendix A3.2).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

Diagnosis of meningococcal infection is carried out by taking an anamnesis, detailed clarification of complaints, clinical examination, additional (laboratory and instrumental) methods of investigation, and is aimed at determining the clinical form, severity of the course, identifying complications and indications for hospitalization, timely routing to a department (box ward, ICU), as well as choosing the optimal patient management tactics.

2.1 Complaints and Anamnesis

Meningococcal infection can occur in various forms (localized, generalized) with clinical manifestations depending on the pathogenesis of the disease, as well as a combination of syndromes. Life-threatening forms are generalized due to the high risk of complications (Appendix B. Diagram 1).

Symptoms:

Comments: the presence of pathognomonic symptoms of meningococcal infection against the background of intoxication syndrome in a patient requires a consultation with an infectious disease specialist for timely diagnosis, clarification of the disease form and severity, prescription of specific examinations and treatment, as well as further patient routing.

Comments: manifestations of intoxication syndrome, which in mild nasopharyngitis is moderately pronounced (37.1°C to 38°C), and in IMD (meningitis, meningococcemia) is maximally pronounced (38°C and above) and persists until diagnosis and the initiation of antibacterial treatment.

Comments: manifestations of meningococcal nasopharyngitis, which resolve within 7–10 days without generalization of the disease.

Comments: the presence of severe, diffuse, bursting, constant headache that is not relieved by other analgesics and antipyretics (N02B), accompanied by pronounced intoxication syndrome, nausea, vomiting not related to food intake, and skin hyperesthesia, allows suspecting invasive meningococcal disease (IMD) or meningitis.

Comments: against the background of pronounced intoxication syndrome and severe headache, the presence of nuchal rigidity and positive Kernig's and Brudzinski's signs allows suspecting IMD or meningitis. This is an absolute indication for emergency medical team hospitalization to an infectious disease hospital/department.

Comments: detection of a characteristic exanthem (hemorrhagic, ranging from petechiae to large stellate hemorrhages) on days 1–2 of the disease against the background of pronounced intoxication syndrome allows suspecting IMD or meningococcemia.

Comments: the onset of focal central nervous system (CNS) lesions and general cerebral syndrome, disorientation in space, time, and person, in the presence of pronounced intoxication syndrome and meningeal signs, suggests IMD, meningitis with the development of a complication—acute swelling and edema of the brain (ASEB).

This is an absolute indication for hospitalization by an emergency resuscitation team (ICU team) to an infectious disease hospital intensive care unit (ICU).

Comments: against the background of pronounced intoxication syndrome, the presence of oliguria or ischuria, decreased blood pressure, a characteristic hemorrhagic rash spreading from the palms and soles, and confusion allow suspecting IMD, meningococcemia with the development of a complication—infectious-toxic shock (ITS). Abdominal and limb pain are caused by tissue hypoperfusion and thrombosis of blood vessels of various calibers against the background of progressing disseminated intravascular coagulation (DIC).

This is an absolute indication for hospitalization by an emergency resuscitation team (ICU team) to an infectious disease hospital intensive care unit (ICU).

Comments: against the background of effective etiological and pathogenetic therapy for meningococcal infection, regression of intoxication syndrome, meningeal signs, and hemorrhagic skin rash is observed, which, combined with the normalization of laboratory tests, serves as an indication for discharging the patient from the infectious disease hospital/department for further outpatient follow-up.

Epidemiological history is also of great importance for the diagnosis of MI:

Comments: in the presence of characteristic complaints and initial examination data, as well as residence in organized communities, presence of contacts with catarrhal-respiratory and intoxication syndromes, and lack of vaccination, meningococcal infection should be suspected.

2.2 Physical Examination

Comments: examination of the oropharyngeal mucosa (oral cavity examination using additional instruments)—in 10-20% of cases, diffuse hyperemia, edema of the mucosal membrane, and hyperplasia of the lymphoid follicles of the posterior pharyngeal wall are detected. Mucopurulent discharge is often present on the posterior pharyngeal wall. From days 1-2 of the disease, against the background of pronounced intoxication, the following are detected: hemorrhagic exanthem predominantly on the distal parts of the arms, legs, thighs, and buttocks, rapidly increasing in size (from petechiae to large stellate hemorrhages) and/or meningeal signs (skin hyperesthesia, nuchal rigidity, bilateral Kernig's sign, upper, middle, and lower Brudzinski's signs). In the first hours of the disease, meningeal signs may be negative in isolated meningococcal meningitis and even in combined forms, with maximum expression of meningeal symptoms observed on days 2-3.

The detection of a hemorrhagic rash predominantly on the distal extremities, along with at least one meningeal sign, is an absolute indication for hospitalization in an infectious disease hospital or a boxed ward.

Comments: in the presence of intoxication syndrome and meningeal signs, general cerebral and focal symptoms usually appear from days 3-4 of the disease and indicate delayed diagnosis of IMD and admission of the patient to a specialized hospital, development of meningoencephalitis and/or complications—ASEB, intracranial complications of IMD, or manifestations of septic encephalopathy (which may occur in meningococcemia without meningitis).

The severity of meningococcal meningitis is determined by the development of a complication—ASEB; the patient's level of consciousness is assessed (Glasgow Coma Scale score from 3 to 14, Appendix G1).

The detection of signs of impaired consciousness and disorientation in time, place, and person against the background of intoxication and meningeal syndromes is an absolute indication for hospitalization by an emergency resuscitation team to an infectious disease hospital ICU. Pathological breathing patterns are detected in extremely severe IMD, most often in the case of dislocation syndrome developing against the background of ASEB.

Comments: if meningeal and brain parenchyma involvement is suspected, diagnostic lumbar puncture in a hospital setting is performed with the patient lying on their side, knees drawn up to the chest, and head flexed forward at the L3–L4 lumbar vertebra level, followed by clinical examination of cerebrospinal fluid (microscopic examination of cerebrospinal fluid, cell count in a counting chamber (determination of pleocytosis), determination of cerebrospinal fluid protein level, cerebrospinal fluid lactate level, and cerebrospinal fluid glucose level, microscopic examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), and etiological analysis of CSF: microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), and PCR detection of meningococcal (Neisseria meningitidis) DNA in the cerebrospinal fluid.

Comments: signs of microcirculatory disturbance include pallor, cyanosis, mottled skin, and hypothermia of the distal extremities. Severity assessment (criteria) for generalized invasive meningococcal disease (GIMD) and meningococcemia is performed in patients with signs of ITS and serves as an indication for hospitalization by an emergency medical team (EMT) in an infectious diseases hospital / ICU if the following are detected:

- hemodynamic instability (systolic blood pressure below 90 mm Hg);

- tachypnea (more than 22 breaths per minute);

- progressive thrombohemorrhagic syndrome;

- oligoanuria, anuria;

- acrocyanosis;

- decompensated metabolic acidosis.

The presence of pathological breathing patterns is detected in extremely severe cases of GIMD during the terminal stage of the disease complicated by refractory septic shock (Appendix A3.6, Appendix B. Scheme 2).

2.3 Laboratory Diagnostics

In an infectious diseases hospital / isolation ward, non-specific and specific diagnostic methods are applied at the stage of diagnosis establishment. In the ICU, laboratory diagnostics are performed to assess the severity of inflammation and the degree of vital organ dysfunction.

Non-specific diagnostic methods

Comments: the test is mandatory but non-specific for diagnosis: the detection of leukopenia or leukocytosis beyond reference values accompanied by a neutrophilic shift in the differential leukocyte count (leukogram) indicates a high probability of a bacterial etiology. Generalized meningococcal infection is characterized by leukocytosis of 16.0–40.0×10⁹/L, neutrophilia, and elevated ESR. In meningococcemia complicated by ITS, leukopenia and thrombocytopenia are observed. In cases where bacteriological confirmation of GIMD is lacking despite a "typical" clinical picture (acute onset, fever, hemorrhagic rash), inflammatory changes in the complete blood count may serve as one of the grounds for establishing a clinical diagnosis.

Comments: urinalysis is mandatory but exhibits low specificity and characteristic features for GIMD diagnosis. Mild proteinuria, leukocyturia, and hematuria may occur as manifestations of intoxication and DIC syndrome.

Comments: changes in blood biochemical parameters are non-specific; they help diagnose organ dysfunction, assess the severity of damage, and evaluate the efficacy of ongoing therapy.

Comments: this test is necessary to assess respiratory failure and the degree of tissue hypoperfusion. In GIMD, purulent meningitis, and meningococcemia, metabolic/respiratory acidosis, hypoxemia, hypokalemia, and hypernatremia are detected.

Comments: an increase in blood C-reactive protein (CRP) >2 standard deviations above normal and procalcitonin (PCT) >2 ng/mL indicates the presence of a bacterial infection and correlates with disease severity, risk of septic shock, necessity of ICU admission, and use of extracorporeal hemocorrection methods (selective lipopolysaccharide hemisorption) in intensive care. In the acute phase of GIMD, CRP and PCT levels typically exceed the normal range by tens of times. Serial procalcitonin testing is used to monitor the efficacy of antibacterial and intensive therapy; in combination with clinical assessment, it is recommended for deciding on the discontinuation of sepsis and septic shock antibiotic therapy, which shortens its duration and improves clinical outcomes. Antimicrobial therapy can be discontinued when procalcitonin concentration decreases by 50–90% compared to its peak registered value, provided there is a clear improvement in the patient's general condition. Given the half-life of procalcitonin, repeat concentration testing in the ICU should be performed dynamically every 3–4 days if necessary. An elevated CRP level may persist in some patients even after normalization of PCT levels, which may be associated with local inflammatory reactions of non-bacterial origin or systemic autoimmune processes.

Comments: in GIMD, these changes are observed during the development of ITS and DIC syndrome. Hemostatic parameters change in accordance with the stages of DIC syndrome; the coagulogram (exploratory hemostasis test) is necessary to evaluate the efficacy of ongoing therapy and make adjustments.

Comments: in GIMD, meningococcemia, or the combined form, an increase in endotoxin activity (endotoxin activity assay >0.6) correlates with the severity of the condition, risk of septic shock, need for ICU admission, and application of extracorporeal hemocorrection methods (selective lipopolysaccharide hemisorption) in intensive care. Blood endotoxin activity determination (gram-negative bacterial endotoxin testing) is used to monitor the efficacy of intensive treatment for sepsis and septic shock.

Comments: performing a lumbar puncture (LP) is possible only in the absence of contraindications (Appendix A3.3); if contraindications are present, the procedure is performed in all patients after their condition has stabilized. The changes are non-specific and indicate only a bacterial etiology of meningitis. Qualitative characteristics of the cerebrospinal fluid (CSF)—color, transparency—and quantitative characteristics—pleocytosis during microscopic examination of the cerebrospinal fluid, cell counting in a counting chamber (determination of cytosis), and measurement of protein, glucose, and lactate levels in the cerebrospinal fluid—are evaluated. In invasive meningococcal disease (IMD) and purulent meningitis, changes in color (white, yellow, green, milky), transparency (turbid), and elevated levels of total protein (up to 1.5–6.0 g/L), lactate (up to 4.1–22.3 mmol/L), and fibrin D-dimer (up to 736–3110 ng/mL) are observed, along with a decreased glucose level (less than 1.5 mmol/L) and, microscopically, neutrophilic pleocytosis (greater than 50%). In the first hours of the disease and when LP is performed at later stages, pleocytosis may be mixed.

Specific diagnostic methods

Comment: microbiological (culture) examination of posterior pharyngeal mucus for meningococcus (Neisseria meningitidis) makes it possible to verify the etiological diagnosis of nasopharyngitis and establish N. meningitidis carriage. For generalized forms of meningococcal infection, if N. meningitidis is not detected in sterile body fluids (blood/CSF), the detection of meningococcus by microscopic examination of posterior pharyngeal smears for meningococcus (Neisseria meningitidis) or by microbiological (culture) examination of posterior pharyngeal mucus for meningococcus (Neisseria meningitidis) cannot serve as a basis for definitive verification of the etiological diagnosis; however, it is an important factor in choosing antibiotic therapy, which should contribute both to the treatment of the systemic disease and to the eradication of meningococcus from the nasopharyngeal mucosa.

Comments: microbiological (culture) examination of blood for sterility / cerebrospinal fluid for meningococcus (Neisseria meningitidis) serves as the "gold standard" for the etiological diagnosis of the disease. Blood samples must be collected as quickly as possible from the time of the patient's admission to the hospital, prior to the initiation of antibiotic therapy. Microbiological (culture) examination of blood for sterility is especially important in situations where there are contraindications to performing a lumbar puncture. In any form of meningococcal infection, culture of the biological medium (microbiological (culture) examination of blood for sterility / cerebrospinal fluid for meningococcus (Neisseria meningitidis)) reveals the growth of Neisseria meningitidis (reliably in the absence of prior systemic antibacterial therapy). Isolation of a Neisseria meningitidis culture and serotyping are sufficient to confirm the diagnosis of invasive meningococcal disease (IMD). This method makes it possible to assess the susceptibility of the pathogen to systemic antibacterial drugs. The identified regional susceptibility of meningococci to systemic antibacterial drugs will allow for the timely adjustment of etiological therapy.

The absence of pathogen growth does not rule out a meningococcal etiology of the disease, especially in cases where the collection of biological material was preceded by the administration of antibacterial therapy.

Comments: the detection of characteristic intracellular Gram-negative diplococci upon microscopic examination of the cerebrospinal fluid for meningococcus (Neisseria meningitidis) indicates invasive meningococcal disease (IMD) and can serve as the basis for initiating specific antibacterial therapy; however, verification of meningococcal infection strictly requires additional methods: bacteriological (culture) (microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis) and blood cultures for sterility) and PCR (molecular genetic) testing of blood/CSF (molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)), and the detection of meningococcal DNA in CSF/blood (determination of Neisseria meningitidis DNA in blood and cerebrospinal fluid by PCR) in the presence of the clinical presentation of invasive meningococcal disease (IMD) allows for the verification of the disease etiology with a high degree of probability.

Comments: the test system used for latex agglutination assay (LA) in the diagnosis of bacterial meningitis makes it possible to detect antigens of meningococci A, B, C, and W. The detection of antigen in CSF in the presence of the clinical picture of invasive meningococcal disease (IMD) allows for the verification of the disease etiology with a high degree of probability. Up to 30% non-specific false-positive (+) and false-negative (-) results are possible; therefore, in addition to LA, the results of culture (bacteriological) and molecular biological (PCR) methods (microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis) and blood cultures for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)) must be taken into account. In cases of discrepancy between LA data and the results of the molecular biological (PCR) method (molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)) or microbiological (culture) methods (microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis) and blood cultures for sterility), preference is given to the latter for the verification of the etiological diagnosis. However, in the presence of a characteristic clinical presentation, it is a highly informative and compelling method for establishing a presumptive diagnosis of invasive meningococcal disease (IMD) and prescribing empiric antibiotic therapy.

Comment: nucleic acid amplification is performed by detecting Neisseria meningitidis DNA in blood and cerebrospinal fluid (conventionally sterile fluids) by PCR. In invasive meningococcal disease (IMD), the detection of meningococcal genome fragments in CSF and blood (Neisseria meningitidis) is absolute confirmation of the diagnosis of meningococcal infection. For rapid diagnosis of meningococcal meningitis, it is recommended to perform real-time multiplex PCR testing of CSF with the capability of simultaneous identification of a wide range of pathogens for differential diagnosis. Panels for "syndromic diagnosis" of neuroinfections by multiplex PCR in a rapid format within 60 minutes have been developed and are available for use; they are intended for the simultaneous identification of 14 pathogens, including Neisseria meningitidis. The cumulative sensitivity of the method is 94.2%, and the cumulative specificity is 99.8%. The average duration of DNA circulation in CSF and blood is up to 3–5 days with adequate antibacterial therapy.

Comments: blood testing (determination of antibodies to the meningococcal pathogen (Neisseria meningitidis) in the blood by IHA is performed after completed treatment, at the time of patient discharge, provided that Neisseria meningitidis was not detected in the blood/CSF (via microbiological (culture) examination of blood for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)) at the time of hospital admission. A negative result is possible.

Comments: in case of negative results of bacteriological (culture) and molecular genetic (PCR) studies of CSF and blood (microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), microbiological (culture) examination of blood for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis) (often against the background of antibiotic therapy administered prior to hospitalization), the diagnosis of meningococcemia or a mixed form of IMD can be established clinically in the presence of characteristic clinical and laboratory manifestations (acute onset, hyperthermia, characteristic hemorrhagic rash, leukocytosis and thrombocytopenia in the hemogram, elevated CRP and PCT levels, manifestations of SIRS).

During the stage of etiological, pathogenetic, and symptomatic therapy

Comments: the frequency of performing a complete blood count and blood parameters is at the discretion of the attending infectious disease physician or critical care specialist. Normalization of laboratory parameters indicates the effectiveness of the ongoing etiological and pathogenetic therapy or allows for its adjustment.

Comments: serial monitoring (frequency) is carried out during the course of treatment depending on the severity of the condition and the presence of abnormal parameters. If clinically indicated, the frequency of general clinical biochemical blood analysis, coagulogram (exploratory hemostasis screening) and blood procalcitonin level testing is at the discretion of the attending infectious disease physician or critical care specialist.

Normalization of laboratory parameters indicates the effectiveness of the ongoing etiological and pathogenetic therapy or allows for its adjustment.

Comments: serial monitoring (frequency) is performed during the course of treatment depending on the severity of the condition and the presence of parameter abnormalities to assess treatment efficacy or to adjust treatment: in moderately severe cases—on days 7–10 of treatment; in severe cases—on days 3, 5, and 7 of treatment. If clinical and laboratory indications are present, the frequency of microscopic examination of the cerebrospinal fluid, cell counting in a counting chamber (determination of pleocytosis), general (clinical) analysis of the cerebrospinal fluid, and determination of protein, glucose, and lactate levels in the cerebrospinal fluid, as well as fibrin D-dimer in the CSF, is at the discretion of the attending infectious disease physician or critical care specialist. Normalization of laboratory parameters in the CSF by the time of discharge from the hospital (color - colorless, transparency - complete, protein - less than 0.45 g/L, lymphocytic pleocytosis below 100 per µL, glucose above 2 mmol/L, lactate less than 3.0 mmol/L) indicates the effectiveness of the ongoing etiological and pathogenetic therapy (Appendix A3.7, Appendix A3.8).

Comments: the frequency of follow-up tests in IMD patients depends on the severity of the disease and the location of hospitalization (isolation ward / ICU)—in moderately severe cases, on days 7–10 of treatment; in severe cases, on days 3–5 of treatment. The question of repeat CSF examinations (using microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), serological examination (latex agglutination test)) should be decided on an individual basis; the advisability of repeat lumbar punctures should be based on the dynamics of clinical manifestations, neuroimaging data (to rule out intracranial complications), and the persistence or absence of laboratory signs of SIRS (CRP and procalcitonin levels).

During treatment, a follow-up examination of blood/CSF at the time of hospital discharge (via microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), microbiological (culture) examination of blood for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis), serological examination (latex agglutination test)) showing the absence of the pathogen isolated upon admission (Neisseria meningitidis) indicates the effectiveness of the ongoing etiological therapy and the clearance of the pathogen from the body.

2.4 Instrumental Diagnostics

Instrumental diagnostic methods in patients with IMD allow for an additional assessment of disease severity and the detection of specific and nonspecific complications.

Comments: Brain CT and brain MRI are advanced imaging modalities used selectively in patients with generalized forms of meningococcal infection with focal neurological signs to assess the state of cerebral structures (affected areas of the brain parenchyma, their size and location, diagnosis of specific complications), severity of cerebral edema (narrowing of CSF spaces), and signs of midline brain shift. To clarify the nature of CNS lesions, urgent examination is indicated for patients with suspected space-occupying brain lesion (tumor), acute cerebrovascular accident, intracranial hematoma, ventriculitis, acute hydrocephalus, or atypical CSF findings.

To rule out a secondary origin of purulent meningitis (post-traumatic, secondary to ENT pathology), brain CT is the method of choice. The advantages of brain CT include rapid scanning and feasibility in mechanically ventilated patients without requiring special non-magnetic equipment. Brain MRI allows a more detailed evaluation of brain tissue and cerebral vessels, but requires specialized equipment and takes significantly longer. Normalization of imaging findings indicates the efficacy of the ongoing etiological and pathogenetic therapy or the need for its adjustment.

Comments: generalized meningococcal infection can be complicated by atypical primary and secondary pneumonia. In the ICU, it is used to monitor the position of the central venous catheter.

If baseline instrumental diagnostic results show abnormalities, serial follow-up studies may be indicated; the frequency depends on the severity of the patient's condition. Normalization of the test results reflects the efficacy of ongoing etiological and pathogenetic therapy or guides its adjustment.

Comments: tachycardia is characteristic of these patients; ECG and echocardiography (EchoCG) help detect signs of cardiac involvement (myocardial and conduction system abnormalities) typical of generalized forms of meningococcal infection. In addition, myocardial contractility and cardiac output parameters are taken into account when assessing the severity of infectious-toxic shock and are used to guide therapy. If baseline instrumental findings are abnormal, repeat evaluations may be indicated. The frequency of follow-up tests in patients with generalized forms of meningococcal infection depends on the severity of their condition, detected abnormalities, and the care setting (isolation ward / ICU). Normalization of the findings indicates the efficacy of ongoing etiological and pathogenetic therapy or the need for its adjustment.

2.5 Other Procedures

Comments: patients with generalized forms of meningococcal infection may develop complications such as acute cerebral edema and herniation in meningitis, or infectious-toxic shock in meningococcemia, especially with delayed hospitalization (later than day 4 of illness); the appearance of early signs is an absolute indication for transfer to the intensive care unit (ICU).

Comments: for patients with generalized forms of meningococcal infection, consultations with subspecialists are performed electively when clinically indicated.

Differential diagnosis

Comments: in nasopharyngitis - differential diagnosis from other nasopharyngeal infections (ARVI); a presumptive diagnosis is only possible during an outbreak in a community and requires laboratory confirmation (microbiological (culture) examination of posterior pharyngeal wall swabs for Neisseria meningitidis).

The presence of meningeal signs accompanied by intoxication syndrome must be differentiated from other conditions associated with pleocytosis, primary and secondary purulent meningitis, viral serous meningitis, tuberculous meningitis, as well as meningism in acute febrile illnesses (influenza), exogenous and endogenous intoxications, cerebrovascular disorders, space-occupying lesions, and CNS abscess. At the same time, clinical differences are quantitative and do not allow for a differential diagnosis without blood and CSF testing using microbiological (culture) methods, latex agglutination assay (LAA), or molecular genetic methods (PCR) (specifically, microbiological (culture) examination of cerebrospinal fluid for Neisseria meningitidis, microbiological (culture) blood test for sterility, molecular biological testing of blood and cerebrospinal fluid for Neisseria meningitidis, which will confirm the diagnosis.

In the presence of hemorrhagic rash against the background of intoxication syndrome, differential diagnosis should be made with rickettsioses, hemorrhagic fevers, leptospirosis, influenza (capillary toxicosis), as well as sepsis of various etiologies, toxic-allergic (drug-induced) dermatitis, hemorrhagic vasculitis, acute leukemia, and in some cases during the first hours of the rash, with childhood infections (rubella, measles). The main differential feature of meningococcemia is the appearance of a hemorrhagic rash during the first day of illness, whereas in other diseases the hemorrhagic rash appears later than the 3rd day of the disease (Appendix A3.4).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

For the provision of medical care, only those methods, medical devices, materials, and medicinal products that are authorized for use in the established manner may be used.

The principles of treatment for patients with generalized forms of meningococcal infection involve simultaneously addressing several goals: arresting the underlying process caused by the pathogen; preventing and treating complications; and preventing the development of residual effects to achieve a complete and sustained recovery.

The choice of treatment tactics is influenced by the following factors:

• clinical form of the disease;

• severity of the disease;

• patient's age;

• presence and nature of complications;

• comorbid conditions;

• availability and feasibility of providing treatment in accordance with the required level of medical care.

Treatment methods

The choice of treatment method depends on the clinical presentation, severity of symptoms, severity of the patient's condition, and presence of complications.

Patient treatment includes:

• Regimen (outpatient / inpatient);

• Nutrition.

Pharmacotherapeutic methods: etiotropic therapy (systemic antibacterial drugs); pathogenetic therapy agents, including detoxification, vasopressor, hormonal, antioxidant, dehydrating, membrane-stabilizing, neuroprotective, and hemostatic therapy to correct metabolic and water-electrolyte disturbances; intensive care and resuscitation methods (urinary catheterization for fluid balance monitoring, placement of a nasointestinal tube for enteral nutrition, mechanical ventilation if necessary, oxygen therapy, anti-shock and anti-edema therapy, hemosorption).

Non-pharmacological treatment methods:

- physical temperature-lowering methods (ice pack to the head);

- toilet of the upper respiratory tract (nasal passages);

- disposable convective warming blanket (to maintain a constant temperature range of 37–38 °C);

- prevention of pressure ulcers at necrosis sites (inflatable alternating-pressure mattress in various configurations, heel, elbow, and sacral cushions);

- room aeration;

- hygienic measures.

Aetiotropic therapy for localized forms of meningococcal infection (nasopharyngitis, meningococcal carrier state)

For the eradication of N. meningitidis carrier state:

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

For the treatment of localized forms of meningococcal infection:

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: for the eradication of N. meningitidis carrier state and in the treatment of localized forms of meningococcal infection, medium-therapeutic doses of systemic antibacterial drugs active against N. meningitidis are used, most frequently: antibiotics – broad-spectrum penicillins (J01CA) – ampicillin**, amoxicillin**; penicillin combinations, including combinations with beta-lactamase inhibitors (J01CR) in oral formulations. In most cases, the following are used: amoxicillin + clavulanic acid** (250 mg + 125 mg 3 times/day) (J01CR), third-generation cephalosporins (J01DD) (Cefixime 400 mg once daily), fluoroquinolones (ciprofloxacin** 500 mg 2 times/day, levofloxacin** 500 mg 1 time/day). The duration of treatment is in accordance with the instructions for use of the drugs in combination with gargling (Chlorhexidine** 0.05% solution, benzyldimethylmyristoylaminopropylammonium, nitrofurazone).

Aetiotropic therapy in the treatment of generalized forms of meningococcal infection

3.1 Conservative Treatment

3.1.1 Etiotropic (antibacterial) therapy (ABT)

Comments: in generalized forms of meningococcal infection proceeding without infectious-toxic shock, intramuscular administration of drugs is acceptable; when infectious-toxic shock develops, only intravenous administration is permissible, because under conditions of tissue hypoperfusion, intramuscular administration does not achieve the systemic effects of the therapy.

Comments: systemic administration of high doses of systemic antibacterial drugs is necessary to ensure their therapeutic concentrations in the intrathecal space.

Comment: antibacterial drugs (ATC classification: Antimicrobial drugs for systemic use) in patients with invasive meningococcal disease (empirical therapy) should be administered only in severe progressive condition of the patient, provided there is vascular access and established infusion therapy, when rapid (up to 90 minutes) hospitalization of the patient is impossible and there are signs of developing complications (cerebral edema, infectious-toxic shock). If rapid transportation of the patient to a hospital is possible, prior to initiating empirical therapy, it is advisable to collect material for bacteriological (culture) testing (including microbiological (culture) examination of cerebrospinal fluid and posterior pharyngeal wall mucus for meningococcus (Neisseria meningitidis), microbiological (culture) examination of blood for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)).

For the use of third- and fourth-generation cephalosporins, meropenem**, ciprofloxacin** - Level of Recommendation C (Level of Evidence – 4)

For ampicillin**, benzylpenicillin** - Level of Recommendation C (Level of Evidence – 5)

Comments: currently, the first-line drugs for the treatment of invasive meningococcal disease (pre-hospital, empirical, etiological therapy) are third-generation cephalosporins (J01DD) – ceftriaxone**, cefotaxime** at maximum daily doses intravenously for 7-10 days, followed by a control lumbar puncture on days 7-10 for moderate severity and on days 3-5-7 for severe meningococcal meningitis. When prescribing ceftriaxone**, it is essential to consider that its use with calcium-containing solutions is contraindicated. The duration of antibacterial treatment (efficacy) depends on the severity of the disease and the presence of complications, and is determined dynamically based on clinical (regression of clinical symptoms), CSF (decrease in neutrophilic pleocytosis, protein and lactate levels), and hematological (decrease in leukocytosis, procalcitonin level) parameters, with mandatory follow-up microbiological (culture) and molecular genetic (PCR) studies of blood and CSF for meningococcus (microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), microbiological (culture) examination of blood for sterility, molecular biological examination of blood and cerebrospinal fluid for meningococcus (Neisseria meningitidis)).

Meropenem** is not a first-line drug for generalized forms of meningococcal infection; it is prescribed in cases of secondary bacterial complications in ICU patients (taking into account the susceptibility of isolated pathogens; it is the drug of choice for empiric prescription in pronounced neutropenia).

Comments: each hour of delay in antibacterial therapy from the moment of admission increased the chance of a fatal outcome by 1.04 times [75]. Each additional hour from the moment of admission to the emergency department until the administration of the first dose of a systemic antimicrobial drug increased mortality in patients with infectious-toxic shock by 1.14 times [75].

Comment:in patients with generalized forms of meningococcal infection, the pharmacokinetic parameters of other beta-lactam antibacterial drugs (J01D)undergo significant changes, leading to the creation of subtherapeutic concentrations. Unlike intermittent administration, which involves infusing each dose in less than 30 min, a prolonged infusion of other beta-lactam antibacterial drugs (J01D)lasting longer than half of the dosing interval, is able to maintain a constant concentration of other beta-lactam antibacterial drugs (J01D). Prolonged infusions of other beta-lactam antibacterial drugs (J01D) lead to reduced mortality. To rapidly achieve an effective concentration of other beta-lactam antibacterial drugs (J01D) administration of a loading dose is required [79].Appendix A3.7.

3.1.2 Pathogenetic and symptomatic therapy

Pathogenetic therapy

Comments: intensive care is carried out against the background of previously performed therapeutic measures and must be timely. In acute swelling and edema of the brain, and infectious-toxic shock in the ICU, tracheal intubation with mechanical ventilation, catheterization of the subclavian and other central veins, urinary bladder catheterization, and placement of a nasogastric tube are performed.

Comment: the volume and composition of infusion therapy are determined by the leading clinical syndrome, taking into account laboratory parameters (complete blood count [CBC], general clinical biochemical blood test, study of acid-base balance and blood gases)) and functional examination (electrocardiography (ECG) and measurement of central venous pressure and right atrial pressure (CVP). Early initiation of crystalloid therapy (ATC code: B05BB, Solutions affecting the water-electrolyte balance) in severe forms of meningococcal infection (HFMI) complicated by infectious-toxic shock leads to a reduction in mortality. Infusion therapy, especially at the initial stage of treatment, shoulders personalized, and a fixed-volume infusion prescription approach does not improve clinical outcomes. It is recommended to initiate fluid administration with a volume of 7 ml/kg over 30–60 minutes against the background of careful patient monitoring (hemodynamic response, urine output rate, gas exchange status). In case of increased tachypnea or decreased saturation, the rate of infusion therapy should be reduced, and conversely, an increase in the infusion rate should be considered if signs of hypoperfusion persist and respiratory function is unimpaired. An important characteristic of balanced crystalloids (ATC code: B05BB) is a reduced chloride ion concentration (typically less than 110 mmol/L) compared to 0.9% sodium chloride solution** (chloride concentration 154 mmol/L at a normal plasma concentration of 95–105 mmol/L) and, thus, a strong ion difference (SID 24–29 mmol/L) close to physiological values. The latter is calculated as the difference cNa+ – cCl^- [2, 3, 4, 82, 83, 84].

Comments: administered intravenously by drip at a rate of 1-4.5 ml/min (up to 90 drops per minute). The average daily dose is 10 ml/kg. The course of therapy is up to 11 days. The volume and duration depend on the severity of the patient's condition. Contraindicated in pregnancy and breastfeeding.

Comment: as a definition of "large volume" of crystalloids (ATC code: B05BB, solutions affecting the electrolyte balance), it is proposed to use the threshold of the daily cumulative balance exceeding 5% of the actual body weight, i.e., more than 50 ml/kg for the first 24 hours. An additional reference point for prescription is a decrease in plasma albumin concentration (more than 10 g/L) over the first 24 hours and blood albumin less than 30 g/L.

Comment: norepinephrine** acts primarily via α1- and β1-receptors, having virtually no effect on increasing heart rate, while stimulating venous vasoconstriction, which mobilizes a significant blood volume, increasing venous return and preload. Stimulation of β1-receptors enhances myocardial contractility, contributing to an increased stroke volume, which together increase diastolic blood pressure, thereby improving coronary artery perfusion pressure. Delay in the administration of norepinephrine** is associated with a significant increase in 30-day mortality. Doses are adjusted individually [90, 91].

Comment: epinephrine** is the second-line vasopressor of choice in refractory septic shock and high doses of norepinephrine** (> 0.5 mcg/kg/min in patients without marked tachycardia) and/or its unavailability. At low doses, epinephrine** mediates its activity predominantly through β1-receptors, which is accompanied by increased myocardial contractility and decreased systemic vascular resistance. High doses have a significant effect on α1-receptors, thereby increasing systemic resistance and cardiac output, and may be accompanied by an increased risk of arrhythmias and splanchnic circulation disorders. When comparing norepinephrine** and epinephrine**, no differences were found in 90-day mortality rates and vasopressor-free days (ATC code: C01CA, adrenergic and dopaminergic agents). Doses are adjusted individually.

Comments: Sepsis-induced myocardial dysfunction is considered the main factor of hemodynamic instability and is associated with worse outcomes in patients with septic shock. Inotropic therapy is used after volume resuscitation in patients with persistent hypoperfusion and myocardial dysfunction, manifested by a decrease in cardiac index below 2.5 L/min/m² and ejection fraction below 35%, a decrease in central venous oxygen saturation (ScvO2) below 70%, an increase in veno-arterial carbon dioxide partial pressure difference (Pv–aCO2) above 6 mmHg, and hyperlactatemia above 2 mmol/L. There are no data supporting the superiority of dobutamine** over epinephrine**. Both drugs should be discontinued if there is no improvement in perfusion or if side effects develop.

Comment: Criteria for refractory septic shock: 1. Requirement for vasopressor support at a dose of more than 0.5 mcg/kg/min of norepinephrine equivalent to maintain mean arterial pressure above 65 mmHg for more than 12 hours. 2. Lack of responsiveness to fluid challenge determined by conventional methods. Other signs include: (1) persistent hyperlactatemia or decreased lactate clearance in the absence of severe liver dysfunction, thiamine deficiency, use of epinephrine**, and lactate-containing solutions (Electrolytes, ATC code: B05BB01); (2) persistent metabolic lactate acidosis poorly corrected by fluid therapy, vasopressor, and inotropic support; (3) marked diastolic hypotension (diastolic BP <50 mmHg in the absence of aortic valve dysfunction); persistent microcirculatory disorders refractory to ongoing therapy; (4) global increase in vascular permeability / capillary leak; (5) fluid accumulation syndrome – an increase in cumulative fluid balance in parallel with deteriorating organ function. Drugs are used in various combinations, doses are adjusted individually.

Comment: in the development of shock resistant to therapy with adrenergic and dopaminergic agents (in the development of acute adrenal insufficiency), systemic glucocorticoids (H02AB) can accelerate the resolution of septic shock, with an increase in vasopressor-free days (Adrenergic and dopaminergic agents, C01CA); however, glucocorticoids contributed to the development of neuromuscular weakness and had no distinct effect on mortality. It has been suggested to initiate hydrocortisone** administration when the norepinephrine** dose equals or exceeds 0.25 – 0.5 mcg/kg/min for more than 4 hours. In the development of Waterhouse-Friderichsen syndrome, the drug dosage is selected individually [13, 36, 38, 55, 64, 65, 67, 82, 93, 95, 96, 97, 112, 113, 114]. The prophylactic use of glucocorticoids in IMID without signs of septic shock is not indicated.

Comment: despite the reduction in mortality with the use of polyclonal intravenous immunoglobulins (J06B) and immunoglobulin M-enriched intravenous immunoglobulins (J06B), the quality of evidence is considered low, and the studies were single-center and had a high risk of bias; therefore, it is recommended to refrain from the empirical use of intravenous immunoglobulins in adults [68]. At the same time, the possibility of using immunoglobulins should be considered in confirmed hypogammaglobulinemia.

Comments. In the subgroup of patients with AKI stage 2 or 3 according to the Acute Kidney Injury Network (AKIN) classification, lower mortality was observed with sodium bicarbonate** therapy: control – 63%, sodium bicarbonate** – 46%; absolute risk reduction (ARR) – 17.7% (–33.0– 2.3), p = 0.016 [69].

Comment: in a multicenter study involving 400 patients with severe metabolic acidosis (pH ≤ 7.20), two groups were compared: intravenous administration of 4.2% sodium bicarbonate** to achieve an arterial blood pH of 7.3 and a control group (without sodium bicarbonate**). There were no differences in mortality between the groups, but hypernatremia, hypocalcemia, and metabolic alkalosis were more frequently observed with the use of sodium bicarbonate** [69].

Comments. The formation of gastrointestinal stress ulcers significantly worsens treatment outcomes in critically ill patients [98]. A randomized controlled trial found no effect of stress ulcer prophylaxis on mortality, but demonstrated a reduction in the incidence of gastrointestinal bleeding [99]. A recently published systematic review identified the following risk factors for clinically significant GIB: coagulopathy, shock, and chronic liver disease [100].

- Single-component sorbed bifidobacterial probiotic (**2-3 capsules (500 million CFU/capsule) 2 times a day for 7-10 days).

- Bifidobacterium bifidum + Lactobacillus plantarum (2 capsules of 50 million CFU + 50 million CFU or powder sachet for oral administration) 3 times a day. Course – 10-15 days.

- Linex® Forte (combination of Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12)) 1 capsule (1 caps. contains 60 mg of Probio-tec AB Blend 64 powder, containing 25.74 mg of Lactobacillus acidophilus (CHR. HANSEN LA-5 ®) and 3.06 mg of Bifidobacterium animalis subsp. lactis (CHR. HANSEN BB-12®)) 1-3 times a day depending on symptom severity.

- Bifidobacterium longum + Enterococcus faecium (1 capsule (containing at least 1×107 CFU Enterococcus faecium ENCfa-68, at least 1×107 CFU Bifidobacterium longum BB-46) × 2-3 times a day for 10–21 days).

- Saccharomyces boulardii (1–2 capsules of 250 mg twice daily during systemic antibiotic therapy)

in patients with acute enteric infections of mixed or unspecified etiology (AEIMUE) with gastrointestinal diseases, functional gastrointestinal disorders receiving prolonged antibacterial therapy for the prevention of Clostridium difficile-associated diarrhea [28, 64, 82, 109, 110, 111].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: probiotics (antidiarrheal microorganisms, ATC code: A07FA) are prescribed as part of combination therapy in the early stages of AEIMUE treatment. The use of agents that regulate intestinal microflora balance (antidiarrheal microorganisms, ATC code: A07FA) in combination with systemic antibacterial drugs or other pathogenetic agents is permitted. They are used for the prevention of intestinal dysbiosis of various etiologies, including those developed during and after systemic antibiotic therapy, leading to disruption of normal intestinal microflora with a deficiency of bifidobacteria, lactobacilli, or normal Escherichia coli, and antibiotic-associated diarrhea; for the restoration of intestinal normoflora during the convalescence period after AEIMUE.

Comment: in patients with AEIMUE complicated by ITS and multiple organ dysfunction, acute renal failure develops in 80% of cases. Renal replacement therapy (RRT) and extracorporeal blood correction (EBC) methods (A18.05.002 Hemodialysis, A18.05.003 Blood hemofiltration, A18.05.006.001 Selective lipopolysaccharide hemadsorption) are recommended not only for organ function replacement, but also to reduce the severity of systemic inflammatory response syndrome (SIRS). An improvement in treatment outcomes has been demonstrated in patients with AEIMUE complicated by ITS when using continuous blood hemofiltration (A18.05.003.001) / prolonged blood hemofiltration (A18.05.003.002) / hemodiafiltration. A personalized approach to establishing indications for RRT is necessary: to decide on the choice of RRT method, it is recommended to evaluate the patient's clinical status, severity of organ dysfunction, availability of the method and experience in its application in a specific clinical situation, and blood endotoxin testing as a criterion for initiating the procedure and treatment efficacy. The use of continuous blood hemofiltration (A18.05.003.001) / prolonged blood hemofiltration (A18.05.003.002) is recommended in hemodynamically unstable patients with AEIMUE complicated by ITS. Contraindications for RRT include ongoing massive bleeding and the patient's terminal state [102].

Comment: extracorporeal cytokine elimination in patients with septic shock using hemoperfusion (selective lipopolysaccharide hemadsorption) helps reduce norepinephrine requirements**, decrease procalcitonin and endothelin-1 levels. The necessity of early initiation of hemoperfusion has been noted; each hour of delay in starting extracorporeal therapy increased mortality risk by 1.5% (p = 0.034). Several studies have demonstrated the efficacy of extracorporeal lipopolysaccharide sorption (LPS sorption) in septic shock. A significant decrease in vasopressor and inotropic requirements (adrenergic and dopaminergic agents, ATC code: C01CA), C-reactive protein, procalcitonin, and other inflammatory markers during hemoperfusion has been revealed. When performing hemosorption (hemodialysis with selective plasma filtration and adsorption, A18.05.002.004), it is necessary to consider the risks of losing systemic antibacterial drugs, hormones (systemic corticosteroids – hydrocortisone**, dexamethasone**), nutrients, anti-inflammatory mediators, and a number of other substances.

Comment: hemoperfusion (hemodialysis with selective plasma filtration and adsorption / selective lipopolysaccharide hemadsorption) is currently used in patients with IMD complicated by septic shock and an endotoxin activity level > 0.6 IU. The use of this treatment method has revealed a statistically significant reduction in 28-day mortality in the group receiving selective lipopolysaccharide hemadsorption (LPS sorption) (A18.05.006.001) compared to standard treatment. Each hour of delay in initiating extracorporeal therapy increased the risk of mortality by 1.5% [47]. It is performed with mandatory dynamic monitoring of Gram-negative bacterial endotoxin (LPS) and the procalcitonin test (blood procalcitonin level assay), which can be considered as laboratory criteria for the efficacy of the therapy [102, 103, 104]. Taking into account the half-life of procalcitonin, repeating its concentration assay dynamically every 3–4 days is advisable.

Comments: there are no absolute contraindications to the administration of corticosteroids. Indications include IMD and meningitis complicated by acute neurogenic brain edema. The use of glucocorticoids (dexamethasone**) in bacterial purulent meningitis does not affect mortality rates, but it reduces the incidence of sensorineural hearing loss provided they are administered before the initiation of antibacterial therapy.

Comments: purulent inflammation of the cerebral meninges causes an increase in intracranial pressure and the development of cerebral edema, the severity of which determines the clinical condition. Therapy is performed under the control of water-electrolyte balance, central venous pressure, circulating blood volume, and hematocrit for no more than 2–3 days, and thereafter as indicated. The optimal regimen is moderate hemodilution (hematocrit 35%).

Comments: mechanical ventilation in the moderate hyperventilation mode.

Comment: medications approved in clinical practice are used, taking into account the period and form of the disease.

Symptomatic therapy

Comments: starting therapy from the pre-hospital stage is carried out using benzodiazepine derivatives (N05BA): diazepam** 10–20 mg IV is used, and if necessary, the dose is repeated after 3–4 hours. At the hospital stage, depending on the duration and nature of the seizures, various antiepileptic drugs (N03A) are used; valproic acid preparations** (N03AG01), barbiturates (N05CA), and other nervous system drugs (N07XX) are most frequently used: sodium oxybate** 20% intravenously at a calculated dose of 70–120 mg/kg of body weight, for debilitated patients – 50–70 mg/kg of body weight as an anti-shock agent for a sedative and hypnotic effect, simultaneously with thiopental sodium** (75–125 mg intravenously over 10 minutes, in case of seizures during local anesthesia – 125–250 mg over 10 minutes), valproic acid** up to 1.5 g/day. Appendix A3.8.

3.2 Surgical Treatment

Performed as needed: tracheotomy, subclavian and other central vein catheterization, excision of skin necroses (necrectomy) in IMD and meningococcemia.

Comments: surgical methods are used as needed – necrectomy, opening and drainage of phlegmon (abscess) in cases of secondary soft tissue infection; in the development of deep necroses and mummification of the distal extremities as a consequence of meningococcemia or disseminated intravascular coagulation (DIC) syndrome.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Basic principles of rehabilitation:

Medical rehabilitation in the reconvalescence period is carried out in medical organizations of the state healthcare system or their respective structural subdivisions, including centers for restorative medicine and rehabilitation, as well as sanatorium-resort treatment according to the profile.

Requirements for the regimen of work, rest, treatment, or rehabilitation

- restriction period – at least 30 days;

- procedure for lifting restrictions – discharge upon clinical recovery or removal from dispensary follow-up;

- recommendations for the patient – restriction of sun exposure (insolation), dispensary follow-up for 1 year, restriction of physical activity for 3 months, restriction of dietary salt, prohibition of alcohol.

Comments: it is important to adhere to the basic principles of rehabilitation: the comprehensive nature of restorative measures involving various specialists and utilizing a variety of intervention methods; maintaining sequence and continuity of the measures performed to ensure continuity at various stages of rehabilitation and dispensary monitoring; rehabilitation and restorative measures must correspond to the adaptive and reserve capabilities of the patient.

5. Prevention and Dispensary Observation

Prevention of meningococcal infection must be comprehensive; only a combination of non-specific and specific preventive measures ensures a reduction in morbidity [1, 2, 3, 5, 6, 7, 8, 9, 12, 17, 47, 53].

5.1 Nonspecific prophylaxis of meningococcal infection

Non-specific prevention is carried out in accordance with the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On the Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (along with "SanPiN 3.3686-21. Sanitary Rules and Norms..."). Preventive measures in the focus of infection are aimed at active case-finding and isolation of patients until their symptoms completely disappear. Following the hospitalization of a patient with generalized meningococcal infection or suspected meningococcal infection, a 10-day quarantine is imposed in the focus. An initial examination (consultation) by an otolaryngologist is performed for individuals who have been in close contact with the patient in order to identify cases of acute nasopharyngitis.

Comments: drugs recommended by the WHO for chemoprophylaxis in foci of meningococcal infection (for individuals over 18 years of age) and in accordance with the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On the Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (along with "SanPiN 3.3686-21. Sanitary Rules and Norms..."):

Refusal of chemoprophylaxis is documented in the medical records and signed by the responsible person and the medical worker.

5.2. Specific prophylaxis of meningococcal infection

Vaccines for the prevention of meningitis (ATX code: J07AH) are not included in the mandatory immunization schedule and are used only according to epidemiological indications, in the event of an impending epidemic surge (an increase in incidence caused by the prevailing meningococcal serogroup by two or more times compared to the previous year). Mass immunization (with coverage of at least 85%) is carried out during an increase in incidence caused by serotypes A, C, W, and Y above 20.0 per 100,000 population.

When meningococcus is detected via microbiological (culture) examination of mucus from the posterior pharyngeal wall for meningococcus (Neisseria meningitidis) in individuals within the focus, vaccination is performed using polysaccharide meningococcal vaccines (ATX: J07AH, Vaccines for the prevention of meningitis) containing antigens of Neisseria meningitidis serogroups A, C, W, and Y, or conjugated with diphtheria toxoid. If determining the meningococcal serogroup is not feasible, emergency immunoprophylaxis is performed without identifying it, using multi-component vaccines for the prevention of meningococcal infection (ATX: J07AH, Vaccines for the prevention of meningitis). Immunization of contacts is carried out in accordance with the vaccine package insert. Vaccination of contacts is carried out in foci of meningococcal infection within the first 5 days after contact [2, 4, 5, 6, 9, 10, 12, 15, 16, 17, 49, 53, 57, 64]. Administration of systemic antibacterial chemoprophylaxis is not a contraindication for immunization.

Comments: according to the resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On the Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (along with "SanPiN 3.3686-21. Sanitary Rules and Norms..."), individuals with an increased risk of infection with generalized meningococcal infection who are subject to vaccination in the inter-epidemic period according to epidemiological indications have been defined:

• individuals subject to conscription for military service;

• individuals departing to areas endemic for meningococcal infection (pilgrims, military personnel, tourists, athletes, geologists, biologists);

• medical workers of structural units providing specialized medical care in the profile of "infectious diseases";

• medical workers and laboratory staff working with live meningococcal culture;

• residents and staff of inpatient social service institutions;

• with round-the-clock stay (infant homes, orphanages, boarding schools);

• individuals living in dormitories, hostels, hotels;

• individuals participating in mass international sports and cultural events;

• children under 5 years of age inclusive;

• adolescents aged 13-17 years;

• individuals over 60 years of age;

• individuals with primary and secondary immunodeficiency states, including HIV-infected individuals;

• individuals who have undergone cochlear implantation;

• individuals with cerebrospinal fluid leakage;

• individuals with functional or anatomical asplenia;

• individuals with properdin and complement component deficiencies.

Immunization is carried out using vaccines against meningococcal infection (polysaccharide monovaccines, bi-vaccines, tetra-vaccines, and conjugated with diphtheria toxoid (Vaccines for the prevention of meningitis, ATX code: J07AH) containing purified inactivated meningococci of serotypes A, B, C, W, Y.

For the Russian Federation, relevant options include polysaccharide mono- and bi-vaccines (A, C) and multi-component vaccines conjugated to diphtheria or tetanus toxoid: A, C, W, Y.

Types of vaccines against meningococcal infection:

1. polysaccharide vaccine for the prevention of serotype A meningococcal infection** 2. polysaccharide vaccine for the prevention of serotypes A and C meningococcal infections** 3. polysaccharide conjugated vaccine for the prevention of serogroups A, C, W, Y, X meningococcal infection** 4. polysaccharide conjugated vaccine for the prevention of serogroups A, C, W, Y meningococcal infection** 5. recombinant (rDNA) subunit adsorbed vaccine for the prevention of meningococcal infection caused by Neisseria meningitidis serogroup B**.

Immunization with any meningococcal vaccine (Vaccines for the prevention of meningitis, ATX code: J07AH) leads to a rapid (from the 5th to the 14th day) rise in antibodies. In almost 100% of people, protective antibody levels against meningococci develop 10 days after the administration of a single dose of the vaccine (Vaccines for the prevention of meningitis, ATX code: J07AH). Even in the event of exposure to the pathogen, a single dose of the vaccine is able to protect the vaccinated person if administered up to 5 days after contact with meningococcus. The vaccination schedule in adults includes a single intramuscular injection. The age from which the meningococcal infection vaccine (J07AH) can be administered is 9 months (polysaccharide conjugated vaccine for the prevention of meningococcal infection of serogroups A, C, W, Y, X; polysaccharide conjugated vaccine for the prevention of meningococcal infection of serogroups A, C, W, Y) and starting from 1 year for polysaccharide vaccine for the prevention of serotype A meningococcal infection**. According to currently available data, the duration of post-vaccination immunity persistence is 3 years.

Immunization of contacts is carried out in accordance with the package insert of each of the listed vaccines for the prevention of meningitis (J07AH). Chemoprophylaxis is not a contraindication for immunization.

Contraindications to vaccination with meningococcal vaccines (Meningitis vaccines, ATX code: J07AH) include: pronounced, severe systemic reactions to a previous vaccine administration (anaphylactic reactions); hypersensitivity to any component of the vaccine; acute infectious diseases or exacerbation of a chronic process.

Vaccination can be carried out 1-2 weeks after achieving remission or recovery from an acute infectious disease.

Information about the performed vaccination (date of administration, drug name, dose, batch number, control number, expiration date, nature of the reaction to the vaccination) is entered into the established medical record accounting forms and the certificate of preventive vaccinations.

Vaccination against meningococcal infection can be carried out simultaneously with vaccination against other infectious diseases, except for vaccination against yellow fever and tuberculosis. The vaccines are administered with different syringes into different body sites.

5.3 Clinical follow-up (dispensary observation)

In accordance with the Decree of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On the approval of sanitary rules and norms SanPiN 3.3686-21 'Sanitary and epidemiological requirements for the prevention of infectious diseases'" (together with "SanPiN 3.3686-21. Sanitary rules and norms...") discharge from the hospital of convalescents with generalized meningococcal infection or meningococcal nasopharyngitis is carried out after clinical recovery and a negative microbiological (culture) blood test for sterility and a microbiological (culture) test of cerebrospinal fluid for meningococcus (Neisseria meningitidis).

Comments: dispensary monitoring is not established for individuals who have had localized forms of meningococcal infection.

For patients who have suffered a severe course of invasive meningococcal disease (IMD), meningitis, or meningococcemia, the timing of dispensary monitoring and the list of necessary examinations and specialist consultations depend on the leading pathological syndromes in the acute period of the disease, no later than one month after discharge from the hospital, with follow-up visits at 1, 3, 6, 9, 12 months, or more frequently and longer if necessary.

If the patient was discharged with residual neurological symptoms, a dispensary visit (examination, consultation) by a neurologist is performed 14 days after discharge, with subsequent monitoring as necessary.

If the patient was discharged with residual cardiac symptoms, the examination is performed 14 days after discharge, with a mandatory dispensary visit (examination, consultation) by a cardiologist.

In the absence of any clinical and laboratory deviations from normal values, convalescents of invasive meningococcal disease (IMD) can be removed from the registry with a recommendation to be exempt from heavy physical labor and sports for 3 months.

Comments: this is due to the fact that with earlier preventive vaccination against other infectious diseases, possible complications of the underlying disease may be interpreted as its consequences. The necessary interval between vaccinations is determined by a physician (general practitioner, infectious disease specialist), taking into account the degree of risk of developing complications of the disease. The risk of contracting rabies and tetanus outweighs any possible complications from vaccination.

6. Organization of Medical Care

The choice of the conditions for providing medical care (outpatient/inpatient), methods and scope of therapy for meningococcal infection are determined by the clinical form of the disease, severity grade, and the presence of complications.

Indications for hospitalization in a medical organization for meningococcal infection are:

- suspicion of a generalized form of meningococcal infection;

- the need to isolate a patient with a localized form according to epidemiological indications.

Detection of patients with generalized forms of meningococcal infection is carried out by physicians of all specialties, mid-level medical personnel of medical and preventive, wellness and other organizations, regardless of legal form, physicians and mid-level medical personnel engaged in private medical practice, during all types of medical care, including when the population seeks medical care, when providing medical care at home, and during appointments with privately practicing physicians.

Medical care for patients with generalized forms of meningococcal infection is provided in the form of:

• primary health care: outpatient, calling a doctor to home (in conditions not providing for round-the-clock medical observation and treatment);

• emergency, including specialized, medical care: during transportation in an ambulance, including an intensive care unit (ICU) team when hospitalizing severe patients;

specialized, including high-tech, medical care in inpatient settings in infectious disease hospitals/departments with ICU (under conditions ensuring round-the-clock medical observation and treatment).

Primary health care for patients includes:

• primary pre-medical health care;

• primary medical (physician-led) health care;

• primary specialized health care.

Primary pre-medical health care for patients in outpatient settings is carried out in all medical institutions and establishments where medical posts are provided. If a physician is present in these institutions, medical care is provided in the form of primary medical health care.

Also, primary medical care is provided by a general practitioner (district general practitioner), general practitioner (family doctor) in outpatient settings, including when calling a doctor to home.

If a generalized form of meningococcal infection is suspected or detected in a patient , immediate hospitalization for treatment in a specialized hospital is required.

Primary specialized health care for patients is provided by an infectious disease physician of a medical organization providing medical care in an outpatient setting (polyclinic, medical consultative center).

Specialized, including high-tech, medical care is provided in an inpatient setting by infectious disease specialists and other medical specialists and includes the diagnosis, treatment of diseases and conditions requiring the use of special methods and complex medical technologies, as well as prevention and medical rehabilitation.

Treatment of patients with generalized forms of meningococcal infection is carried out in a specialized hospital setting upon referral by a district general practitioner, general practitioner (family doctor), infectious disease specialist, medical personnel of an emergency medical team (emergency medical paramedic, emergency team physician, emergency physician), who detected the infectious disease, or inpatient specialists of any profile.

The choice of conditions for medical care (outpatient/inpatient), methods, and scope of therapy for meningococcal infection are determined by the clinical form of the disease, severity grade, and presence of complications.

Indications for hospitalization in a medical organization:

Comments: only in the case of meningococcal infection, meningococcal nasopharyngitis, or detected carriage with a laboratory-confirmed diagnosis (microbiological (culture) study of mucus from the posterior pharyngeal wall for meningococcus (Neisseria meningitidis) is the treatment of the patient on an outpatient basis permitted provided that:

• the patient lives in a separate, well-appointed apartment;

• there is no contact at the place of residence with workers of medical and preventive, children's, and equivalent organizations;

• patient care and compliance with all anti-epidemic regime measures are ensured;

• the patient has no clinical manifestations of the generalized form of meningococcal infection;

• dynamic clinical medical observation and laboratory testing at home are ensured;

• exclusion criteria for outpatient treatment: living in boarding schools, hotels, hostels, etc., or a history of allergic reactions to systemic antibacterial drugs of choice in the treatment of meningococcal infection.

Comments: given the rapid disease progression and high risk of life-threatening complications in GFMI, hospitalization to an infectious diseases hospital by an ambulance emergency team is mandatory.

If symptoms of acute brain swelling and herniation (ABSH) or infectious-toxic shock (ITS) are identified, immediate hospitalization by an ambulance intensive care team (ICT) to an ICU (or intensive care wards) must be carried out for intensive monitoring and emergency/resuscitation measures until stabilization.

Early pre-hospital diagnosis of GFMI (up to day 3 of the disease), timely hospitalization of patients to an infectious diseases hospital, and adequate antibacterial and pathogenetic therapy contribute to a favorable prognosis and reduced mortality [2, 11, 13, 24].

6.1 Indications for admission to the intensive care unit (ICU):

Comments: in GFMI, severity and the threat of life-threatening complications (ABSH, ITS, DIC syndrome) are indicated by:

- rapid progression of general cerebral symptoms, hemodynamic disturbances, hemorrhagic syndrome, multiorgan dysfunction;

- impaired consciousness;

- skin cyanosis;

- early appearance (within the first 10 hours) of characteristic hemorrhagic rash, its rapid progression, and localization on the chest, neck, face;

- increasing tachypnea > 22 breaths per minute;

- drop in blood pressure below the age-appropriate norm;

- decreased urine output (diuresis less than 40 ml/hour);

- clinical and radiological signs of pulmonary edema, including acute respiratory distress syndrome in adults;

- manifestation of other vital complications as part of SIRS;

- decrease in prothrombin index (PTI) below 70%, prolonged activated partial thromboplastin time (aPTT), thrombin time exceeding 15 sec., decreased fibrinogen, INR, indicating hypocoagulation and DIC syndrome (stages 2-4 of ITS);

- decompensated metabolic acidosis (pH < 7.25);

- hypoxemia ($paO_2$ _{less than} 60-70 mm Hg with $FiO_2$ _exceeding 50%);

- progressive thrombocytopenia (less than 100 × 10³/µl);

- elevated blood creatinine (above 400 µmol/l) and urea (above 40 mmol/l).

The aforementioned manifestations in GFMI are an absolute indication for emergency hospitalization to the ICU within 30 minutes to administer immediate intensive/resuscitation therapy. (Appendix A3.6, G1, G2).

6.2 Indications for discharge from the medical organization

For normalization of CSF parameters in general (clinical) CSF analysis, upon evaluating CSF lactate, glucose, and protein levels. Grade of recommendation C (level of evidence – 5)

For the regression of clinical pathognomonic symptoms of GFMI, normalization of complete blood count (CBC) parameters, negative results of molecular biological examination of CSF and blood for meningococcus (Neisseria meningitidis). Grade of recommendation C (level of evidence – 4)

Criteria for recovery (clinical, laboratory) in GFMI, meningitis [2, 5, 12, 13, 67]:

• persistent normalization of body temperature for 5 days or more;

• absence of hemorrhagic skin rash;

• absence of headache, nausea, vomiting;

• absence of meningeal signs (nuchal rigidity, Kernig's, Brudzinski's signs);

• absence of focal CNS signs;

• absence of clinical manifestations of pulmonary, joint, or eye involvement;

• normalization of CSF parameters upon investigation: physical properties (colorless, complete transparency) of CSF, microscopic examination of CSF, cell count in a counting chamber (determination of pleocytosis) - lymphocytic pleocytosis below 100 per 1 µl and lymphocytes > 70% in the smear, evaluation of lactate (less than 3 mmol/l), glucose (above 2 mmol/l), and protein (less than 0.45 g/l) levels in CSF;

• normalization of general clinical blood chemistry parameters (reference values for urea, creatinine, electrolytes (potassium, sodium), alanine aminotransferase, aspartate aminotransferase, glucose level (above 2 mmol/l));

• normalization of leukocytes and ESR in the complete blood count (CBC) with differential white blood cell count (leukocyte formula);

• absence of meningococcal growth in follow-up microbiological (culture) examination of CSF for meningococcus (Neisseria meningitidis) (culture), absence of meningococcal DNA (Neisseria meningitidis) in molecular biological blood testing for meningococcus (Neisseria meningitidis) (PCR);

• absence of radiological signs of pulmonary involvement.

Criteria for antimicrobial therapy (AMT) efficacy and recovery based on CSF data in patients with meningococcal meningitis are presented in Appendix A3.8.

Criteria for recovery (clinical, laboratory) in GFMI, meningococcemia:

• persistent normalization of body temperature for at least 5 days or more;

• regression of hemorrhagic rash;

• normalization of blood pressure;

• normalization of urine output (diuresis);

• absence of clinical manifestations of pulmonary, cardiac, joint, or ocular involvement;

• normalization of coagulogram parameters (screening hemostasis test) (reference values for fibrin D-dimer, fibrinogen, aPTT);

• normalization of acid-base balance and blood gas parameters;

• normalization of complete blood count (CBC) parameters with differential white blood cell count (leukocyte formula): leukocytes, platelets, and ESR normalization;

• absence of meningococcal culture growth (Neisseria meningitidis) in follow-up microbiological (culture) blood sterility testing and absence of meningococcal DNA in molecular biological blood testing for meningococcus (Neisseria meningitidis) (PCR);

• stabilization of condition on electrocardiography (ECG);

• absence of radiological signs of pulmonary involvement.

7. Additional Information

Despite the fact that clinical diagnosis of GFMI in typical cases is not difficult, due to the similarity of clinical symptoms with a number of other acute diseases accompanied by hemorrhagic rash and CNS involvement, it remains a challenge in pre-hospital care for GFMI patients. Late diagnosis, underestimation of severity, and delayed hospitalization in a specialized hospital adversely affect the course and outcome of the disease, as evidenced by the high percentage of patients in severe condition at the time of hospitalization: ICU admission rates increased from 38% in 2010 to 69% in 2025, with adults accounting for the majority (82%). This indicates a growing trend in the number of patients with severe (complicated) disease courses due to delayed admission to a specialized hospital and a high risk of death. The causes of severe condition and ICU admission in GFMI patients were: brain edema-swelling and/or infectious-toxic shock.

Prognosis and outcome of the disease depend on many factors [2, 12, 13, 24]:

1) severity of condition at admission – 38% to 69% are hospitalized in the ICU.

2) quality of pre-hospital care: early diagnosis, assessment of severity, prompt hospitalization in a specialized hospital, antibacterial therapy in severe condition and delayed medical seeking.

3) quality of diagnosis and treatment in a specialized hospital setting (inpatient): which consists of rapid diagnosis of the disease form, assessment of the severity of the condition with subsequent adequate routing (box ward or ICU), comprehensive etiological diagnosis (microbiological (culture) examination of posterior pharyngeal mucus for meningococcus (Neisseria meningiditis), microscopic examination of cerebrospinal fluid for meningococcus (Neisseria meningiditis), bacteriological examination of CSF/blood ( upon microbiological (culture) examination of cerebrospinal fluid for meningococcus (Neisseria meningitidis), microbiological (culture) examination of blood for sterility), serological examination of CSF - latex agglutination test (LAT), detection of meningococcus (Neisseria meningitidis) DNA in cerebrospinal fluid by PCR), the rapid results of which primarily allow choosing the correct patient management tactics, selection of optimal antibacterial, intensive, pathogenetic therapy and early evaluation of its effectiveness; determining the optimal duration of treatment, as well as qualified and high-quality care for patients with invasive meningococcal disease.

Due to the spread and frequent (up to 50%) diagnosis of invasive meningococcal disease caused by N. meningitidis serotype W (a hypervirulent strain belonging to sequence type ST-11 (clonal complex cc11)), atypical (hypertoxic form) and rare forms of the disease have begun to be observed more frequently, presenting diagnostic difficulties upon initial medical presentation: pneumonia, endo-/myocarditis, arthritis, osteomyelitis, enteritis, peritonitis, fasciitis, epiglottitis, colpitis, urethritis [3, 4, 13, 16, 19, 21-23, 28, 51, 53, 54].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Beloborodov V.B. - MD, Professor of the Department of Clinical Microbiology, National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya.

2. Vengerov Yu.Ya. - MD, Professor of the Department of Infectious Diseases and Epidemiology, Russian University of Medicine of the Russian Ministry of Health.

3. Vilnits A.A. - MD, Head of the Research Department of Emergency Intensive Care, Senior Researcher at the Department of Neuroinfections and Organic Pathology of the Nervous System, Pediatric Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency, Associate Professor at the Department of Infectious Diseases in Children, Faculty of Retraining and Professional Development, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

4. Gorelov A.V. - Academician of the RAS, Professor, Deputy Director for Science, Central Research Institute of Epidemiology of Rospotrebnadzor, Head of the Department of Infectious Diseases and Epidemiology, Russian University of Medicine of the Russian Ministry of Health.

5. Nagibina M.V. - MD, Professor of the Department of Infectious Diseases and Epidemiology, Russian University of Medicine of the Russian Ministry of Health.

6. Novak K.E. - PhD in Medicine, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

7. Usenko D.V. - MD, Head of the Educational Center, Leading Researcher at the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor.

8. Uskov A.N. - MD, Associate Professor, Head of the Department for the Organization of Medical Care for Adults, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia.

9. Chentsov V.B. - PhD in Medicine, Head of the Intensive Care Unit, Infectious Diseases Clinical Hospital No. 2 of the Moscow Healthcare Department.

10. Chulanov V.P. - MD, Professor, Deputy Director for Scientific Work and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health.

11. Esaulenko E.V. - Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

All members of the working group are members of the Pokrovsky National Association of Infectious Disease Specialists (NAIDS).

The authors of the clinical guidelines confirm the absence of financial support/conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

In these clinical guidelines, all information is ranked by the level of reliability (evidence) depending on the quantity and quality of studies on the issue and taking into account search results in electronic databases.

Target audience of the clinical guidelines:

1. Infectious disease specialist;

2. General practitioner (internist);

3. Neurologist;

4. General practitioner (family physician);

5. Ambulance physician;

6. Emergency department physician;

7. Anesthesiologist-resuscitator;

8. Medical students, residents, postgraduate students, trainees of faculty for advanced training.

Determination of levels of evidence and grades of recommendation for diagnostic interventions

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

¹ The generally accepted standard for clinical studies of diagnostic interventions is a cross-sectional study design, in which the diagnostic method under investigation and the reference method—serving as the "gold standard" for diagnosing the disease or condition under study—are applied in parallel and under identical conditions to each enrolled patient. The study and reference methods must be applied independently of each other (i.e., the test method cannot be part of the reference method) and must be interpreted by the investigator without knowledge of the results of the other method (blinding is recommended). 

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing levels of recommendation persuasiveness (LRP) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Related Documents

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 157-FZ of September 17, 1998, "On Immunoprophylaxis of Infectious Diseases";

2. Federal Law No. 326-FZ of November 29, 2010, "On Compulsory Medical Insurance in the Russian Federation";

3. Federal Law No. 321-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation";

4. Order of the Ministry of Health and Social Development of Russia No. 494 of August 9, 2005, "On the Procedure for Using Medicinal Products in Patients for Vital Indications";

5. Order of the Ministry of Health and Social Development of Russia No. 804n of October 13, 2017, "On Approval of the Nomenclature of Medical Services";

6. Order of the Ministry of Health and Social Development of Russia No. 69n of January 31, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases";

7. Order of the Ministry of Health of Russia No. 205n of May 2, 2023, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers";

8. Order of the Ministry of Health of Russia No. 700n of October 7, 2015, "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education";

9. Order of the Ministry of Labor of Russia No. 585n of August 27, 2019, "On Classifications and Criteria Used in Carrying Out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise";

10. Order of the Ministry of Health of Russia No. 203n of April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care";

11. <Letter> of Rospotrebnadzor No. 01/9620-0-32 of June 29, 2010, "On the Interaction of Territorial Bodies and Institutions of Rospotrebnadzor with the Reference Center for Monitoring Bacterial Meningitis";

12. Order of the Ministry of Health of Russia No. 375 of December 23, 1998, "On Measures to Strengthen Epidemiological Surveillance and Prevention of Meningococcal Infection and Purulent Bacterial Meningitis";

13. "MR 3.1.2.2516-09. 3.1.2. Prevention of Infectious Diseases. Respiratory Tract Infections. Epidemiological Surveillance of Meningococcal Infection. Methodological Guidelines" (approved by the Chief State Sanitary Doctor of the RF on May 25, 2009);

14. Resolution of the Chief State Sanitary Doctor of the RF No. 4 of January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (along with "SanPiN 3.3686-21. Sanitary Rules and Norms..."). 

Appendix A3.1. Symptoms and Clinical Criteria for the Diagnosis of Meningococcal Nasopharyngitis, Meningitis, Meningococcemia

Appendix A3.2. Complications of generalized meningococcal infection

Appendix A3.3. Contraindications for lumbar puncture:

- impaired level of consciousness (GCS less than 9 points) or fluctuating consciousness;

- relative bradycardia and hypertension,

- focal neurological symptoms,

- seizures,

- unstable hemodynamics,

- inadequate pupillary reaction to light, doll's eye sign,

- septic shock,

- progressive hemorrhagic rash,

- hemostatic disorders,

- platelet count less than 100 x 10⁹/L,

- ongoing anticoagulant therapy,

- local skin and soft tissue infection at the site of lumbar puncture,

- respiratory failure.

Transportation/hospitalization of a patient with symptoms of progressive ABSE due to the potential development of life-threatening conditions must be carried out exclusively by an ICU team (intensive care unit team) provided that mechanical ventilation is performed.

Appendix A3.4. Differential diagnosis of purulent meningitis and meningococcemia

Differential diagnosis of meningococcal meningitis and other diseases with meningeal syndrome

Appendix A3.5. Differential diagnosis of meningococcal infection, meningococcemia, and other infectious diseases presenting with exanthema

Appendix A3.6. Severity criteria for infectious-toxic shock (ITS) complicating GFMI and meningococcemia

Appendix A3.7. Systemic antibacterial drugs used in the treatment of meningococcal infection

Appendix A3.8. Drugs recommended for pathogenetic therapy of GFMI

Appendix A3.9. Cerebrospinal fluid criteria for the efficacy of etiotropic therapy in patients with severe meningococcal meningitis (admission to the ICU)

Appendix B. Physician Action Algorithms

Scheme 1. Algorithm of actions for primary care physicians upon suspicion of generalized meningococcal infection

Scheme 2. Summary schematic algorithm for the management of a patient with suspected generalized form of meningococcal infection (hospital setting).

Appendix C. Patient Information

Meningococcal infection is an acute infectious disease caused by a specific type of bacterium, the meningococcus. It occurs worldwide, with children being affected most frequently. Transmission occurs via airborne droplets, typically during contact in enclosed spaces (childcare facilities, dormitories, military units). Children are susceptible from the first months of life. The incubation period ranges from 3 to 7 days. The infection predominantly presents as asymptomatic carriage or nasopharyngitis (inflammation of the nasopharynx), which is clinically indistinguishable from other acute respiratory infections. Meningococcal carriage and nasopharyngitis lead to the development of immunity. In individuals with increased susceptibility, generalized forms of the disease develop: meningococcemia (acute meningococcal sepsis), meningitis (purulent inflammation of the meninges), and a combined form of the disease featuring both meningococcemia and meningitis. Generalized forms of meningococcal infection are among the frequent causes of death among common infectious diseases. Severe clinical course and unfavorable outcomes are influenced by delayed diagnosis and late admission to a specialized hospital. Meningococcemia begins acutely, with a sudden rise in body temperature accompanied by chills, up to 39–40⁰C and above, body aches, and severe weakness. Within a few hours to a day, a skin rash appears in the form of red spots of various sizes, sometimes up to 2–3 cm, with dark centers. In severe cases of the disease, the temperature drops, and the extremities become cold and cyanotic. Blood pressure decreases. When high temperature appears, emergency medical assistance must be called immediately, and the patient is hospitalized in an infectious diseases hospital. Self-medication and refusal of hospitalization often lead to a fatal outcome. In other cases, against the background of the rash and elevated body temperature, the patient develops a mounting headache that soon becomes unbearable, accompanied by vomiting; loud sounds and bright light cause the headache to intensify. All of the above symptoms indicate the development of meningitis. If such a patient is not hospitalized, symptoms of impaired consciousness will appear within 2–3 days as a result of cerebral edema. In some patients, the rash is absent, and the initial symptoms are elevated body temperature, escalating diffuse headache, and other symptoms of meningitis. Recovery from meningococcal infection without medical assistance is practically impossible. In the infectious diseases hospital, patients with meningococcal infection undergo diagnostic evaluation: a complete (clinical) blood count is performed, and a lumbar (spinal) puncture in the lumbar spine is conducted (the procedure does not pose a threat to the patient's life and health and is mandatory), followed by examination of the cerebrospinal fluid (molecular biological blood test for meningococcus (Neisseria meningitidis), serological method (latex agglutination test), and microbiological (culture) examination of the cerebrospinal fluid for meningococcus (Neisseria meningitidis)). Antibacterial therapy is prescribed, and if necessary, the patient undergoes an initial examination (consultation) by an anesthesiologist-resuscitator. Fatal cases and cases of recovery with residual effects (hearing loss, paralysis, increased intracranial pressure) are most frequently observed in cases of delayed seeking of medical care, refusal of hospitalization, and self-medication. After discharge from the hospital, patients who have suffered from meningococcal infection remain under dispensary observation at the district polyclinic for a year; they are advised to limit physical exertion, high salt intake, and alcohol consumption, and to refrain from excessive sun exposure. Close contacts are placed under observation with screening for meningococcal infection, and vaccination is recommended.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1-GN. Assessment scales, questionnaires, and other patient status assessment tools provided in clinical guidelines.

Appendix G1. Criteria for assessing the severity of generalized meningococcal infection, meningitis

(Glasgow Coma Scale (Teasdale G.M., Jennett B., 1974)).

Russian name: Glasgow Coma Scale.

Original name: Glasgow coma scale.

Type (underline): rating scale.

Source (official website of developers, publication with validation): Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A practical scale. (Eng.) // The Lancet: journal. – Elsevier, 1974. – Vol. 2, no. 7872. – P. 81 – 4. – doi:10.1016/S0140-6736(74)91639-0.-PMID4136544

Purpose: a scale for assessing the depth of coma in adults; consists of three tests evaluating eye opening, verbal, and motor responses. A specific number of points is awarded for each test.

15 points – alert / clear consciousness;

13–14 points – moderate obtundation;

11–12 points – deep obtundation;

9–10 points – stupor;

7–8 points – coma grade 1;

5–6 points – coma grade 2;

3–4 points – brain death (coma grade 3).

Appendix G2. Criteria for assessing the severity of generalized meningococcal infection to determine multiple organ dysfunction (Sequential Organ Failure Assessment [SOFA] scale, developed in 1994).

Russian name: Organ dysfunction severity scale (SOFA).

Original name (if any): Sepsis (sequential) Organ Failure Assessment (SOFA).

Source (official website of developers, publication with validation): Vincent J.L., Moreno R., Takala J., Willatts S., Mendonça A. De., Bruining H., Reinhart C.K., Suter P.M., Thijs L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine // Intensive Care Med. 1996 Jul;22(7):707-10.

Type (underline): assessment scale.

Purpose: assessment of organ dysfunction, mortality risk, and sepsis in intensive care unit (ICU) patients.

Adrenergic and dopaminergic agents (ATC code: C01CA)

Interpretation: the total SOFA score is the sum of all six scores, ranging from 0 to 24.

The higher the score for an individual organ (system), the more pronounced its dysfunction.

The higher the total score, the greater the severity of multiple organ failure

0 points — normal.

4 points — greatest deviation from the normal value.

• the higher the score, the greater the organ dysfunction and the more pronounced the multiple organ dysfunction.

• with a total score of up to 12, multiple organ dysfunctions are suspected.

• 13–19 points — progression of dysfunction to failure is suspected.

• a total score of 20 - 24 indicates a high probability of a fatal outcome.

• in the presence of infection, an increase in the SOFA score by 2 or more points from the baseline value is one of the clinical criteria for sepsis.