Lyme Disease in Adults: Clinical Guidelines

List of Abbreviations

BAS — biologically active substances

LD — Lyme disease

WI – weighted image

WHO – World Health Organization

EP — evoked potentials

DIC – Disseminated intravascular coagulation

ADEM — acute disseminated encephalomyelitis

DNA – deoxyribonucleic acid

VEP — visual evoked potentials

ITBB — ixodid tick-borne borrelioses

PI — pulse sequence

Infectious toxic shock

ELISA – Enzyme-linked immunosorbent assay

TBE — tick-borne encephalitis

LB — Lyme borreliosis

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

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

MME — multiple migratory erythema

MRI – magnetic resonance imaging

EM – erythema migrans

M-CFS – modified complement fixation test

NB – neuroborreliosis

NSAIDs – nonsteroidal anti-inflammatory and antirheumatic drugs

IFA – indirect immunofluorescence assay

CBC – Complete Blood Count

UA – Urinalysis

CHI – Compulsory Health Insurance

MPS – Simple Medical Procedure

PNS – peripheral nervous system

PCR – Polymerase chain reaction

IFA – Immunofluorescence assay

RCTs – randomized controlled trials

HIHA – Indirect hemagglutination assay

CFT – complement fixation test

SM – serous meningitis

SSEP – somatosensory evoked potentials

FL – Federal Law

ACA – chronic atrophic acrodermatitis

CNS – central nervous system

3G C – 3rd-generation cephalosporins

CSF – cerebrospinal fluid

ECG – electrocardiography

ENMG – electroneuromyography

Echo-CG – echocardiography

EEG – electroencephalography

IFN-g – interferon gamma

B.b. – Borrelia burgdorferi

IDSA – Infectious Diseases Society of America 

Ig A, M, G, E – immunoglobulins class A, M, G, E

IL-1, 2, 4, 8 – interleukin 1, 2, 4, 8

ILADS – International Lyme and Associated Diseases Society

Osp A, B, C, D, E, F – outer surface membrane proteins

NICE – National Institute for Health Care & Excellence 

TNF-α – tumor necrosis factor alpha

TBEV – Tick-borne encephalitis virus

Terms and Definitions

Natural focal diseases are a clearly defined group of diseases characterized by specific features of the epidemic process. These are diseases of wild animals whose pathogens possess polypathogenicity and can be transmitted to humans, causing illness.

Natural disease focus is an area of a specific landscape where susceptible warm-blooded vertebrates, the pathogen, and vectors are present, and, given favorable environmental factors, the pathogen circulates. Natural foci exist independently of humans. A natural focus may contain pathogens of several diseases, as well as different species of animals susceptible to these diseases.

Anthropurgic foci (human-made) are foci acting as components of natural foci in areas developed by humans within cities, villages, and other settlements.

Enzooticity (endemicity) is the association with a specific territory and specific climatic and geographical conditions.

Zooanthroponoses are infectious diseases that develop in humans as a result of interaction with an animal population in which the pathogen circulates.

Vector-borne mechanism of infection transmission is a mechanism of infection transmission in which the pathogen is present in the circulatory and lymphatic systems and is transmitted through bites of specific and nonspecific vectors: a bite of a blood-sucking arthropod (insect or tick). It is necessary for the vector to transmit the pathogen directly from the source of infection to a susceptible organism.

Alimentary mechanism of infection transmission is a mechanism of infection transmission in which the pathogen enters a susceptible organism through the mouth, primarily by swallowing food (alimentary route).

Incubation period is the time interval from the moment of infection to the appearance of the first clinical symptoms of the disease.

Cerebrospinal fluid (lat. liquor cerebrospinalis, cerebrospinal fluid, liquor) is the fluid that constantly circulates in the brain ventricles, cerebrospinal fluid pathways, and the subarachnoid space of the brain and spinal cord.

Genospecies: An elementary species.

Cytokines: A group of polypeptide mediators involved in the formation and regulation of the body's defense responses (interleukins, interferons, colony-stimulating factors, chemokines, transforming growth factors, etc.). The main properties of cytokines that unite them into an independent regulatory system include pleiotropism and interchangeability of biological action, an (mostly) inducible nature of synthesis, the absence of antigenic specificity of action, self-regulation of production, and the formation of a cytokine network.

Disease – a disorder of bodily function, working capacity, and the ability to adapt to changing environmental and internal conditions arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Zooanthroponoses are infectious diseases that develop in humans as a result of interaction with an animal population in which the pathogen circulates.

Nosological entity is a set of clinical, laboratory, and instrumental diagnostic features that allow a disease (poisoning, trauma, physiological state) to be identified and classified into a group of conditions with common etiology and pathogenesis, clinical manifestations, and general approaches to treatment and management.

Level of certainty of evidence – reflects the degree of confidence that the found effect of a medical intervention is true.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Lyme disease (synonyms: Lyme borreliosis, Ixodes tick-borne borrelioses, tick-borne borreliosis, Lyme borreliosis, tick-borne systemic borreliosis) is a group of infectious vector-borne natural focal diseases caused by bacteria of the genus Borrelia of the family Spirochaetaceae, transmitted by Ixodes ticks, characterized by polymorphism of clinical manifestations with syndromes of damage to the skin, nervous system, cardiovascular system, internal organs, and musculoskeletal system, with a tendency toward a latent and chronic course [1, 3, 4, 5].

When infected with a single genospecies, the pathological process is considered borreliosis monoinfection. Infection with 2 or 3 borrelia genospecies is considered borreliosis coinfection (mixed infection).

It is advisable to use the term "Lyme disease" specifically for the infection caused by the genospecies Borrelia burgdorferi s.s. Considering these facts, the entire group of tick-borne borreliosis (TBB) nosoforms comprises Lyme disease and clinically undifferentiated tick-borne borrelioses. It should be noted that according to modern taxonomic classification, B. miyamotoi belongs to the tick-borne relapsing fever group and has distinct pathogenetic and clinical features compared to borreliosis caused by the burgdorferi s.l. pathogenic complex [1].

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

Etiology.

The causative agents of ITBB belong to the order Spirochaetales, family Spirochaetaceae, genus Borrelia. They received their generic name in honor of the French microbiologist A. Borrel, who studied this variety of spirochetes in the early 20th century.

Currently, based on differences in DNA nucleotide sequences, more than 18 borrelia genospecies belonging to the B. burgdorferi sensu lato complex are distinguished; representatives of this complex are unevenly distributed within the global nosoarea of this infection. Not all borrelia of this complex are pathogenic to humans. Pathogenicity has been proven for 3 genospecies: B. burgdorferi sensu stricto, B. garinii, B. afzelii. All these genospecies are distributed in Russia (predominantly B. garinii and B. afzelii). Another 6 genospecies have been isolated from humans: B. spielmanii, B. bavariensis, B. valaisiana, B. lusitaniae, B. bissetii, but their role in the development of clinical syndromes has not yet been definitively determined.

These are Gram-negative spirochetes, relatively easily stained with aniline dyes, which distinguishes them from other spirochete genera. Another distinguishing feature of borrelia is the absence of mitochondria and an undulating membrane. The length of the microbial cell ranges from 10 to 30 µm, and the transverse dimension is 0.20–0.25 µm. In shape, they are convoluted, left- or right-handed spirals.

Borrelia have a single linear chromosome and up to 20 circular and linear plasmids, also known as microchromosomes. The protein (antigenic) spectrum of borrelia is highly variable and differs not only among borrelia of different genospecies but also among isolates of the same genospecies.

Borrelia have groups of antigens: surface (OspA, OspB, OspD, OspE, and OspF), flagellar, and cytoplasmic. The flagellar protein (flagellin) with a mass of 41 kDa has cross-determinants with the main myelin protein, cardiomyocyte and synovial membrane proteins, as well as with antigens of certain bacteria, which allows it to cause both autoimmune and false-positive reactions. The cell wall is represented by outer surface proteins: OspA, OspB, OspD, OspE, and OspF, whose antigens are highly variable. The antigenic spectrum of borrelia is variable in different strains of the same genospecies, and the commonality of the antigenic structure of borrelia despite their genotypic variability is 48–70%. Surface lipoproteins determine species affiliation and are the main immunogens. Their greatest heterogeneity is found in B. garinii and B. afzelii. Strains of B. burgdorferi s.s. are distinguished by the relative constancy of the surface protein spectrum. Antigenic similarity between borrelia and host tissues (mimicry) determines the development of autoimmune processes, which are most pronounced in the chronic course. Many antigenic determinants of the outer envelope are similar to those of other borrelia species and even certain bacteria. This explains the possibility of cross-immunological reactions.

The molecular and genetic characteristics of the pathogen determine the polymorphism of clinical manifestations of borreliosis infection. A relative association between the borrelial genospecies and predominant organ involvement has been proven. Musculoskeletal system damage is most commonly caused by the B. burgdorferi sensu stricto genospecies, neurological disorders (neuroborreliosis) are associated with the B. garinii genospecies, and skin lesions, particularly ACA, are most frequently recorded upon infection with the B. afzelii genospecies. Meanwhile, B. afzelii and B. garinii were detected in biopsy specimens from ECM [1].

Borrelia species are cultivated in vitro only in media enriched with amino acids, vitamins, bovine and rabbit plasma albumin, and other substances (modified BSK-II medium). The optimal cultivation temperature is 30–34^°C. Borrelia are characterized by a relatively long and variable growth period in nutrient media under anaerobic conditions, typically ranging from 7 to 20 hours. When the microbial cell count reaches 10⁶–10⁸ per ml, further laboratory studies can be performed. Borrelia grown in culture media keep well at low temperatures (-70° to -90°C) for several years without losing their biological properties. Formalin, phenol, ethyl alcohol, and other disinfectants, as well as ultraviolet radiation, have an inactivating effect on Borrelia.

The lack of genes encoding the synthesis of amino acids, fatty acids, cofactors, and nucleotides in Borrelia explains their high nutritional requirements for cultivation with serum supplements. Furthermore, since Borrelia are chemoorganotrophic anaerobes, they must obtain energy for ATP synthesis from substrate-level phosphorylation, which is available only in the cytoplasm of other cells, as Borrelia lack genes encoding the oxidative phosphorylation electron transport chain. Borrelia also lack other enzymes required for the tricarboxylic acid cycle and phosphorylation. Thus, their own metabolic capabilities are so limited that for survival they must rely on a host organism (with a predominance of intracellular persistence), which ensures the availability of ready-made nutrients. Additionally, Borrelia can form atypical immobile L-forms (or pseudocysts) characterized by reduced metabolic processes, ensuring long-term survival for the pathogen. Upon pseudocyst formation, Borrelia acquire a coiled shape, and surface proteins are altered, allowing the pathogen to evade the host's immune responses. The triggers for pseudocyst formation include high temperatures and the administration of systemic antibacterial agents (specifically, beta-lactam antibiotics such as penicillins). Subsequently, under favorable environmental conditions, pseudocysts can transform back into motile spiral forms. The ability to form L-forms is an important mechanism in the development of chronic infection [1, 3, 4, 5].

Pathogenesis.

Pathogens of the Borrelia burgdorferi sensu lato complex are capable of dissemination and long-term persistence in the human body, which can lead to chronic forms of the disease, as well as a cyclic and variable course of the infection manifested as systemic involvement of target organs—the skin, heart, nervous system, and musculoskeletal system [2, 3, 4, 5].

Borrelia inhabit the gut epithelium of unfed ticks. During blood feeding, Borrelia multiply, enter the hemolymph and salivary glands, and are transmitted with the tick's saliva into the skin of a new host. Infecting spirochetes express decorin-binding protein, through which they attach to proteoglycans. Lacking their own proteases, spirochetes hijack the host's plasminogen activation system to degrade the fibrinogen-rich extracellular matrix. This enables the microorganism to "digest" surrounding tissues, spread within the skin, and penetrate blood vessels. By binding non-immunogenic fibrinolytic proteases, Borrelia employ a novel mechanism of microbial pathogenic action that explains their ability to rapidly disseminate [9, 11, 16].

When the pathogen enters the host organism via tick saliva, a complex of inflammatory and allergic processes may develop at the inoculation site, manifesting as erythema accompanied by regional lymphadenopathy. Multiple clinically significant manifestations of Lyme disease are associated with the presence of live spirochetes that bind to the surface of human cells, triggering a cascade of inflammatory mediator release upon activation [4, 5].

Following the multiplication of the pathogen at the site of entry, lymphatic and hematogenous dissemination occurs to the lymph nodes, internal organs, joints, and central nervous system. This is accompanied by the partial destruction of Borrelia with the release of endotoxin, causing symptoms of intoxication.

Generalization of the infection is clinically manifested by systemic involvement of internal organs—lymph nodes, liver, muscles, cardiovascular and nervous systems, and skin. Borrelia are capable of crossing the blood-brain barrier, inducing the corresponding clinical picture of the disease, namely meningitis, and less frequently, meningoencephalitis.

The ability of Borrelia to persist in the body for a long time leads to a chronic course of the infectious process with involvement of the joints and nervous system.

Regardless of the stage of the infectious process, clinical manifestations are caused by the presence of live Borrelia in the body and spirochetemia. The involvement of various body systems in generalized infection has been proven by numerous animal experiments and studies of intravital organ biopsies and autopsy material [5, 9].

The absence of a cutaneous lesion at the onset is likely associated with the vector-borne transmission mechanism, where a fraction of the Borrelia enters the bloodstream directly [4, 11].

The specific immune response in borreliosis infection is slow. In the early stages of the disease, specific class IgM immunoglobulins are produced, the levels of which reach a maximum by the 3rd–6th^th week of the illness. Specific class IgG antibodies are detected later—their concentration increases 1.5–3–6 months after the onset of the disease [4, 5, 8, 17].

Borrelia can interact with multiple factors of specific and nonspecific human resistance. B. burgdorferi stimulate the production of various inflammatory mediators (IL-1, IL-6, TNF-α) involved in the development of arthritis. Autoimmune reactions are suspected to play a role in the pathogenesis of neuroborreliosis. For instance, monoclonal antibodies have revealed shared antigenic determinants between the 41 kDa flagellar antigen and certain human tissues, specifically peripheral nerve myelin fibers, central nervous system neurons and axons, certain epithelial cells, synovial membrane cells and sinuses, and cardiomyocytes—precisely those organs and tissues most frequently affected in Lyme borreliosis. In patients with acute borreliosis, the concentration of antibodies to denatured DNA, cellular mitochondria, extractable nuclear antigens, and myocardial tissue components increases even at the peak of the illness [4, 14, 17, 19].

In the early stages, fibroblasts, macrophages, endothelial cells, and other body cells produce cytokines, the profile of which may subsequently determine the course and outcome of the infection. It is precisely at this point in the infectious process that cytokines determine the differentiation pathways of T-cell subsets possessing pathogenic potential [10, 11, 15, 16, 52, 53].

The activity of T cells producing a wide range of biologically active substances (BAS) leads to various phenomena. The interaction of immunogenetic factors, activation of immunocompetent cells, formation of the immune response, and manifestation of autoimmune reactions at this stage lead either to the elimination of the pathogen or to the development of various clinical and pathogenetic variants of the infection [10, 18].

Undoubtedly, Lyme disease is an immune-mediated condition. The response of the immune system plays a significant role in the clinical course and outcomes of the infectious process [5–7]. Incomplete phagocytosis in the early stage of pathogenesis, the ability of Borrelia to persist long-term in fibroblasts, and the production of the serine protease BhpA determine the development of relapsing and chronic forms of the disease [8, 17, 20]. To protect themselves from the human immune response, Borrelia can inhibit the complement system via surface proteins (Fhbp, OspE, OspF, Erps) that bind plasma complement regulatory proteins, enhance the synthesis of anti-inflammatory cytokines, bind plasminogen to OspA on their surface, and bind to extracellular matrix components. These very mechanisms account for the ability of Borrelia to undergo recombinational rearrangements of the surface protein antigenic structure during reproduction in the human body, contributing to the phenomenon of immune evasion [2, 5, 8, 16, 54].

The work of numerous domestic and international researchers has proven alterations in various components of the immune system in Lyme disease [1, 2, 6, 8, 10, 12, 15, 16, 18, 55]. The defense response begins with the phagocytosis of microorganisms and a primary inflammatory reaction. Activated phagocytes secrete cytokines with anti-inflammatory (IL-6, IL-8, TNF-α, etc.) and immunostimulatory (IL-1, IL-3, IL-6, IL-12, IL-15, TNF-α) effects.

IL-1 is involved in almost all stages of the immune response. IL-1 activates APCs and CD4+ lymphocytes, influences the differentiation of T and B lymphocytes and other immunocompetent cells. IL-1 activates cytotoxic CD8+ lymphocytes and NK cells, and participates in the regulation of the production of IL-2, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and other cytokines. Active inhibitors of IL-1 production are IL-4, IL-10, IL-12, and TNF-α. IL-3 is a multipotent activator of hematopoietic cells. The immunostimulatory effect of IL-3 has not been sufficiently studied. Its realization is possible through the stimulation of NK cells.

IL-6 regulates B-lymphocyte differentiation and enhances antibody production, and induces cellular cytotoxicity. IL-6 has pronounced pro-inflammatory effects, participates in the generation of LAK cells, and protects neutrophils from apoptosis, enhancing their cytotoxic potential. IL-6 increases the synthesis of C-reactive protein (CRP). CRP, after binding to cell phospholipids, activates a subcomponent of the complement system, triggering a process similar to the classical pathway of complement activation. Subsequent formation of the membrane attack complex results in the lysis of the infected cell. The inhibition of inflammation by interleukin-6 may also be associated with its ability to induce the secretion of the IL-1 receptor antagonist.

IL-8 is produced by many cell types and has pronounced pro-inflammatory properties. The main biological effect of IL-8 is the induction of chemotaxis of neutrophils, eosinophils, basophils, and other cells of the immune system. IL-8 enhances angiogenesis in vivo and in vitro. IL-12 is a multipotent activator of cellular immunity. It enhances the activity of T-killers, NK, and LAK cells. IL-12 activates macrophage cytotoxicity. An important property of IL-12 is the enhancement of FasL expression and the induction of apoptosis. IL-12 inhibits angiogenesis. The anti-angiogenic effect of IL-12 is realized at the level of protein kinase receptors, adhesion molecules, integrins, and other surface structures.

IL-15 is very similar in its biological properties to IL-2 and is largely its synergist, including in the induction of LAK cell activity. IL-15 enhances the anti-inflammatory activity of T-killers and NK cells, the production of cytokines by CD4+ lymphocytes, and can act as a chemoattractant for T lymphocytes.

Activation of endotheliocytes is accompanied by an increase in the expression of ICAM-1 and VCAM-1 adhesion proteins on their membranes and the adhesion of neutrophils, monocytes, and lymphocytes. Upon contraction of the activated endothelium, interendothelial gaps widen, and cells previously fixed to the endothelium rush into them; a primary accumulation of monocytes forms around the vessel, which turn into macrophages of the future granuloma. Macrophages in the inflammation focus begin to produce mediators that attract new effector cells. In addition to cytokine-induced endothelial activation, direct activation by bacterial cells is possible during inflammation. The ability of Borrelia surface lipoproteins to induce the expression of adhesion molecules—E-selectins, ICAM-1, and VCAM-1—on the activated vascular endothelium has been established. Borrelia surface lipoproteins also possess chemotactic properties and the ability to induce monokine secretion.

The ability of Borrelia to perform independent progressive movements in tissues is reflected in the features of local inflammation. In the center of the erythema (at the site of the initial accumulation of the pathogen), Borrelia are exposed to the active influence of inflammatory factors, they lose their mobility, and their number decreases, resulting in a decrease in local inflammation phenomena with the formation of a clearance in the center of the erythema. The appearance of new rings of hyperemia is associated with new generations of Borrelia due to the reduction of inflammatory factors. All this usually leads to the development of a characteristic erythema migrans, which may not even have a annular shape. It has been proven that with incomplete phagocytosis and inadequacy of specific humoral defense mechanisms, favorable conditions are formed for the development of Borrelia persistence [15, 16]. It is also known that in all periods of the disease, many years after infection, live spirochetes can be detected, and therefore systemic antibacterial treatment is indicated in all stages. Etiotropic treatment in the early period for erythema migrans promotes its rapid resolution and prevents the development of late manifestations [5, 17].

In the dissemination stage of Borrelia, hematogenous and lymphogenous spread of the pathogen from the primary focus to other skin areas and internal organs is observed. The ability of Borrelia to directly penetrate through endothelial cells into the vascular lumen cannot be ruled out. The spread of spirochetes can also occur via lymphogenous and perineural routes. Fixed Borrelia cause hyperactivation of the immune system, an excessive cellular and humoral response is formed; activation of T lymphocytes occurs with a subsequent increase in the functional activity of CD8+ cells, leading to the depletion of their population, the complement system, and antibodies, resulting in a state of relative immunodeficiency [2, 4, 5, 7, 15]. Processes associated with the accumulation of specific immune complexes containing Borrelia antigens in the synovial membrane of joints, dermis, kidneys, and myocardium are of substantial importance.

An increase in the level of specific IgM immunoglobulins is observed in the period from 3 to 6 weeks of the disease and is associated with the activation of B lymphocytes. The serum concentration of IgG increases gradually over months, with an increase in the number of Borrelia and, accordingly, their antigens. Lymphocytes and the specific immunoglobulins they produce react at the beginning of the disease selectively to individual Borrelia antigens, both surface and cytoplasmic. As the disease progresses, the spectrum of antibodies to microbial cell antigens expands. The final stage of the functioning of the cellular, humoral links of the immune system and the complement system is the formation of antigen-antibody complexes with their subsequent elimination or lysis. Some researchers associate the long-persisting high level of specific IgM in some patients with Lyme disease with impaired function of T-helper cells, which are necessary for switching IgM production to IgG, which may be due to the use of early antibacterial therapy that weakens the switching of antibody synthesis [2, 4, 23-25].

At the beginning of the disease, lymphocytes and the specific immunoglobulins they produce react selectively to individual surface and cytoplasmic antigens of Borrelia. The main immunogens in the pathogenesis of Lyme disease are Borrelia surface proteins (OspC lipoprotein). As the disease progresses, the spectrum of antibodies to microbial cell antigens expands (OspA, OspB). These lipoproteins are potent inducers of inflammatory reactions, which is especially characteristic of OspA. Persisting for a long time on the surface of Borrelia, they can activate both nonspecific resistance cells (macrophages) and polyclonal cells of the immune system (B and T lymphocytes). Activation of polyclonal B lymphocytes leads to the synthesis of antibodies that cause inflammatory reactions in the corresponding organ. At the same time, the produced antibodies exhibit cross-reactivity with respect to both Borrelia antigens and tissue proteins (e.g., nerve tissue axonal proteins, synovial membrane proteins, etc.). As the disease progresses, autoimmune mechanisms become increasingly significant in the pathogenesis of the disease [4-6, 11, 15, 56].

Circulating immune complexes formed as a result of the interaction of antibodies and Borrelia antigens undergo lysis or elimination by mononuclear phagocytic system cells. An increase in the number of CIC in the blood leads to their accumulation in the synovial membrane of joints, dermis, kidneys, and myocardium. CIC attract neutrophils to tissues, which produce cytokines, biologically active substances, and enzymes causing local inflammatory and dystrophic changes in the affected tissues and organs.

A frequent clinical manifestation of Lyme disease at various pathogenetic stages is damage to the musculoskeletal system: the development of arthritis, tendinitis, bursitis, myositis, etc. In the pathogenesis of arthritis, a fundamental role is played by Borrelia lipoproteins, which stimulate the secretion of IL-1 by monocytic-macrophage cells and cytotoxic T lymphocytes, as a result of which the synthesis of prostaglandins and collagenase by the synovial tissue is triggered, leading to the activation of the inflammatory process in the joints, bone resorption, and cartilage destruction.

At the early dissemination stage, elimination of Borrelia and CIC, residual metamorphosis of the pathological process, and recovery are possible.

To date, the question regarding the mechanisms of long-term persistence of Borrelia in the patient's body remains controversial. The chronic course of the disease with late relapses and prolonged (sometimes exceeding 10 years) persistence of Borrelia in the body leads to irreversible organ damage. Under conditions of an immunodeficient state, reactive-allergic reactions develop, the autoimmune component of inflammation is activated, and persistent degenerative and atrophic processes are formed in the affected organs. The chronic course of the disease is frequently accompanied by damage to the nervous, cardiovascular, and musculoskeletal systems.

Thus, on the part of the host organism, the causes of the chronization of borreliosis infection are an inadequate immune response: weakness of the mechanisms forming a specific immune response and a tendency to form autoantibodies against self-tissues. The main properties of Borrelia that contribute to their persistence are significant resistance to the complement system and antigenic variation.

1.3 Epidemiology of the Disease or Condition

Lyme borreliosis (LB) belongs to the group of natural focal zooanthroponoses with a predominantly vector-borne transmission mechanism. Cases of Lyme borreliosis are registered over a vast territory of Eurasia and are widespread in the forest and forest-steppe zones of Russia (from the Baltic coast to the shores of the Pacific Ocean). The primary epidemic significance as vectors in the territory of Russia belongs to the ticks Ixodes persulcatus and I. ricinus, which are characterized by an extremely wide range of hosts, manifested in the existence of persistent natural foci of infections with the circulation of pathogens between ticks and their hosts. In the central, eastern regions and in certain areas of the forest zone of the European part of Russia, I. persulcatus ticks are most widespread, whereas in the western regions of the country, I. ricinus ticks predominate. In natural foci, LB pathogens circulate between ticks and wild tick hosts, among which there are more than 200 species of wild vertebrates, of which about 130 are small mammals and 100 species of birds. When non-immune animals (mainly small rodents) are infected, the pathogen multiplies in their bodies. Since infection of susceptible animals occurs not simultaneously, but throughout the entire seasonal period of tick activity, they play a significant role, along with vectors, as a reservoir of infection in nature.

Ticks have a 3-stage lifecycle (larva, nymph, and adult), lasting 2–3 years. Larvae emerge from fertilized eggs in late spring and feed once for 2 or more days. The following spring, they molt into nymphs and feed again for 3–4 days. After feeding, nymphs can develop into adults. Spontaneous infection rates of ticks with Borrelia are 5–15 times higher than with tick-borne encephalitis (TBE) virus, which also determines higher incidence rates of this infection.

From the moment a tick crawls onto human clothing until the start of blood-sucking, 1–2 hours elapse. In humans, the tick most frequently attaches in the areas of the neck, chest, armpits, and inguinal folds, i.e., areas with thin skin and an abundant blood supply. A relatively frequent site of tick attachment can be the scalp. Attachment and biting of the tick to the body remain unnoticed in the majority of cases, as its saliva contains anesthetic, vasodilator, and anticoagulant substances. A person's sensation of soreness and itching at the site of tick attachment arises only 6–12 hours later or even later. The blood-engorgement process of female ixodid ticks can last 6–8 days. At the beginning of feeding, the tick can transmit Borrelia only if they are already present in the salivary glands, i.e., in a generalized tick infection (approximately 30–35% of all unfed ticks in nature). When Borrelia are located exclusively in the tick's gut, their transmission is accomplished during the second phase of feeding (later than 1–2 days of attachment). Therefore, early removal of ticks prevents human infection in a number of cases.

Transmission of Borrelia is possible via tick feces if they get onto the skin and are subsequently rubbed into the skin during scratching. Cases of mechanical transmission of Borrelia due to accidental crushing of ticks during their removal from animals (dogs) and the entry of the tick gut contents into microtraumas of the skin or onto the conjunctiva of the eyes are not excluded. Another possible route of pathogen transmission from animals to humans, according to some researchers, may be the alimentary route, realized through the consumption of raw milk (predominantly goat's milk) or dairy products without heat treatment.

The possibility of transplacental fetal infection in pregnant women with borreliosis infection has been proven. The detection of Borrelia in various fetal organs (brain, liver, kidneys) indicates transplacental transmission of the pathogen. However, in none of these cases were there signs of an inflammatory reaction in the affected tissues. Several studies have reported spontaneous abortions, as well as congenital heart defects in fetuses whose mothers were infected with B. burgdorferi during pregnancy. Thus, it is impossible to draw an unequivocal conclusion regarding the causal relationship between the presence of spirochetes and an adverse fetal outcome. In 1985, the first case of transplacental transmission of B. burgdorferi from mother to child was documented. Borrelia were found in the spleen, kidneys, and bone marrow of an infant who died shortly after birth from a congenital heart defect. The newborn's mother had suffered from the erythematous form of borreliosis during pregnancy and had not received treatment [57].

Currently, it can only be stated that pregnant women with a history of tick bites must be informed about the possible outcomes of tick-borne infections. They must undergo prophylaxis for Ixodes tick-borne borreliosis (ITBB) and tick-borne encephalitis. Subsequently, such patients must be monitored throughout the entire pregnancy and after delivery. Children born to such mothers should be screened for tick-borne infections for at least the first two years of life. In the USA, amoxicillin** is recommended for treating pregnant women, whereas in Europe, intravenous ceftriaxone** is used [58, 59, 60].

The incidence rate in particular areas depends on the intensity of the epizootic process, which changes annually depending on a complex of ecological processes occurring in that specific ecosystem.

The annual dynamics of LB incidence is characterized by marked seasonality associated with the vector activity period. Human cases are registered starting from the 2nd–3rd decades of April. The peak incidence occurs in May in the European territory of the country, in May–June in the Cis-Urals, the Urals, and Western Siberia, and in May–July in the Far East. In foci where *I. ricinus* ticks predominantly inhabit, cases of the disease can also be registered in autumn—in September and October—due to the presence of an additional activity period of these ticks in late summer [1, 2, 6, 18, 61].

Thus, the disease is characterized by spring-summer seasonality driven by the period of tick activity, which is related to regional natural-geographic, weather conditions, and vector species.

1.4 Features of Coding the Disease or Condition

In ICD-10, LB is classified under heading A69 "Other spirochetal infections" and includes the code:

A69.2 — Lyme disease

1.5 Classification of the disease or condition

There is no single universally accepted classification of the disease. The clinical polymorphism of Lyme borreliosis is most comprehensively reflected by the clinical classification proposed by Yu.V. Lobzin, A.N. Uskov, and S.S. Kozlov in 2000 [5].

Thus, according to the disease form, manifest and latent forms are distinguished. The manifest form is characterized by clinical symptoms of Lyme borreliosis and the presence of pathogen persistence, whereas latent infection is characterized solely by the persistence of Borrelia in the absence of clinical symptoms of the disease, but with the presence of serological (ELISA) and molecular-genetic (PCR) markers of the infectious process.

According to the clinical marker of the disease in acute and subacute courses, the erythematous form is distinguished in the presence of pathognomonic erythema migrans, and the non-erythematous form in the absence of erythema, but with clinical manifestations of general infectious syndrome. At the same time, each of these forms can proceed with symptoms of organ damage, in particular involving the nervous system, musculoskeletal system, heart, skin, etc.

According to the course, acute, subacute, and chronic Lyme borreliosis are distinguished. The acute course of the infectious process is characterized by a duration of up to 3 ^months, subacute—from 3 to 6 months, and chronic—exceeding 6 months.

Depending on the severity, mild, moderate, and severe courses of the pathological process are distinguished. When determining the severity of the disease, not only the severity of clinical manifestations is taken into account, but also the presence of organ lesions. There is a clear correlation between the severity of Lyme borreliosis and the duration of the disease. The criteria for determining severity are:

• For the acute course: fever intensity below 38˚C lasting up to 3 ^days in mild cases; fever intensity of 38-39.5˚C lasting 3-5 days in moderate cases; fever intensity above 39.5˚C lasting more than 5 days in severe cases.

• For the subacute course: fever intensity decreases regardless of the severity, and body temperature can be normal, subfebrile, or febrile; however, in mild cases, organ lesions are absent, in moderate cases, one system is affected, and in severe cases, two or more systems or functional failure of one of the systems is present.

Chronic infection can be characterized by either a continuous or a relapsing course.

By predominant organ involvement: with lesions of the skin, nervous system, joints, heart, etc.

Clinical manifestations according to the stage of Lyme borreliosis

Stage 1 – localized infection: erythema migrans, non-specific symptoms (fever, arthralgia, myalgia, ossalgia, lymphadenopathy, headache; atypical forms are possible, including diffuse macular erythema, vesicular, and erysipeloid-like forms).

Stage 2 – early organ manifestations: nervous system (meningitis, Bannwarth syndrome, encephalomyelitis, cranial neuropathy, cerebrovascular disorders), myositis, mono- or oligoarthritis, endo-, myo-, or pericarditis, lymphocytoma cutis, hepatitis, ocular lesions (chorioretinitis, uveitis, optic neuritis), glandular tissue involvement (strumitis, parotitis); secondary erythema.

Stage 3 – late (chronic) organ manifestations: skin lesions (acrodermatitis chronica atrophicans, lymphocytoma, plaque-type atrophic scleroderma), nervous system lesions (mono- or polyneuritis, including of cranial nerves, progressive encephalomyelitis, cerebrovascular disorders), joint lesions (mono-, oligo-, or polyarthritis).

1.6 Clinical presentation of the disease or condition

Lyme borreliosis is characterized by significant difficulties in timely clinical diagnosis due to the polymorphism of clinical symptoms combined with a scarcity of pathognomonic manifestations at different stages of the disease. At the present stage of studying this group of diseases, a total of only five pathognomonic clinical manifestations are known: erythema migrans (EM), benign lymphocytoma cutis, acrodermatitis chronica atrophicans (ACA), Bannwarth syndrome, Recklinghausen-Akerman encephalomyelitis, and neurological disorders associated with EM that developed after a tick bite.

Clinical picture of acute Lyme borreliosis

The incubation period of the disease is variable and depends on various factors, such as the infecting dose and individual human host resistance. According to systematic reviews of literature data, the incubation period ranges from 1 to 60 days, averaging 7-14 days. People are highly susceptible to tick-borne borreliosis [4, 5, 11, 21, 70].

The onset of acute tick-borne borreliosis is typically characterized by a pronounced intoxication syndrome manifested by febrile fever (38-39˚C), possible chills, often accompanied by arthromyalgia, myalgia, ossalgia, as well as polylymphadenopathy and hyperhidrosis.

A pathognomonic symptom of the acute course of the disease, which does not require serological confirmation, is erythema migrans (EM) associated with the tick bite site. The clinical course of EM was first described by the Swedish dermatologist A. Afzelius in 1910 and the dermatologist B. Lipschutz in 1913 [22-24]. Regional lymphadenitis generally develops in the area where EM appears. The lymph nodes retain an elastic consistency, are not fused with surrounding tissue, and tenderness upon palpation is rarely noted. EM is characterized as a uniformly saturated bright pink spot, possibly with a cyanotic tint, with central clearing (annular erythema). However, solid (homogeneous) EM is also frequently observed. The dimensions of EM vary quite widely from 2 cm to 70 cm, averaging 15-20 cm [1, 5, 25-27].

The inflammatory lesion may subsequently spread in proximal and distal directions (migration of erythema). The course of erythema migrans is benign in nature and regresses over time (on average, up to 2-4 weeks). In rare cases, EM develops with secondary skin changes – vesicles, hemorrhages, erosions, and necroses [5, 17, 25, 28, 29].

In the non-erythematous form of tick-borne borreliosis, erythema migrans is absent, which presents significant difficulties in the early verification of the infectious process. In such cases, fever may often be the only non-specific clinical manifestation of the disease.

Features of acute tick-borne borreliosis in the Russian Federation include the relatively early development of organ pathology against the background of a general infectious syndrome. Involvement of the nervous system generally consists in the development of general cerebral and focal neurological symptoms (headache, dizziness, positive Mann-Gurvich sign, photophobia, and in some cases, nausea and vomiting). The development of meningeal syndrome is accompanied by nuchal rigidity, and positive Kernig's and Brudzinski's signs.

Central nervous system involvement in the acute course of tick-borne borreliosis is characterized by the development of polyneuropathies in the distal extremities. Sensory disturbances manifest as hyperesthesia and pain syndrome. Motor disturbances manifest as muscle weakness and decreased deep tendon reflexes.

Musculoskeletal system involvement is distinguished by the development of short-term arthralgia and ossalgia. Myalgia is most frequently localized in the neck, shoulder girdle, thighs, and legs.

Cardiovascular system involvement is relatively rare. Cardialgia, arterial hypertension, disorders of cardiac automatism and conduction (I-II degree AV blocks, intraventricular blocks, bundle branch blocks, prolongation of PQ and/or QRS segments, PQ syndrome) are observed [62].

Ocular involvement is rare and can occur at all stages of the infection, manifesting as conjunctivitis, panophthalmitis, chorioretinitis, iridocyclitis, and keratitis. This pathology more frequently develops in the erythematous form of the disease.

It should be borne in mind that the latent form of tick-borne borreliosis has no clinical manifestations.

Particular mention should be made of the pathognomonic symptom complex that can develop in both acute and subacute tick-borne borreliosis – Bannwarth syndrome, characterized by the development of serous meningitis (or meningoencephalitis), pronounced radicular syndrome of the cervical and/or lumbar spine, and mononeuritis of the facial or abducens nerves [30, 31].

Clinical picture of subacute Lyme borreliosis

The subacute course of tick-borne borreliosis is characterized by the development of intoxication syndrome and organ lesions.

Dermatological lesions are most commonly represented by secondary multiple EMs (both homogeneous and annular) not associated with the primary affected site, sometimes with the development of generalized lymphadenopathy, and having smaller dimensions compared to the primary EM – from 5 to 15 cm. In some cases, secondary EMs are combined with ACA, benign lymphocytoma cutis, and other organ manifestations [26-29, 32]. Secondary EMs may be asymptomatic or accompanied by pain, burning, or a sensation of heat.

Neurological manifestations are quite diverse and are largely characterized by involvement of the peripheral nervous system in the form of cranial neuropathies, radiculopathies, peripheral neuropathies, multiple mononeuritis, plexopathies (brachial, lumbosacral), Guillain-Barré-like syndrome, and motor-sensory neuropathy. Bannwarth syndrome may also occur in subacute tick-borne borreliosis. In cases of cranial nerve involvement, the facial nerve (VII pair) is most frequently involved via unilateral neuritis resulting in facial muscle paresis. Neuritis of the trigeminal (V pair), abducens (VI pair), vagus (X pair), accessory (XI pair), and hypoglossal (XII pair) nerves develops less frequently [4, 5, 11, 17].

Arthropathies in the subacute course of tick-borne borreliosis (TBB) can present with arthralgic and arthritic variants of musculoskeletal involvement. Objective signs of joint inflammation are absent in the arthralgic variant. However, myalgia and the development of myositis are possible, predominantly in the cervical and lumbar regions and in the lower extremities [4, 5, 11, 17]. The arthritic variant is characterized by a mono-oligoarticular pattern of involvement affecting large (shoulder, hip, and knee) and medium-sized (elbow, wrist, ankle) joints, accompanied by mild to moderate clinical synovitis. A connection with the tick bite site is often noted. Additionally, the inflammatory process in the joints is characterized by the development of tendinitis and tenosynovitis. As the disease progresses, other joints become involved.

Clinical picture of chronic Lyme borreliosis

The chronic course of the disease develops 6–12 months after infection and is characterized by long-term persistence of borrelia in the body. The chronic inflammatory process affects the musculoskeletal system, skin, peripheral, and central nervous systems. The main manifestations of this stage of the disease are neuroborreliosis, mono- and polyarthritis, and chronic acrodermatitis chronica atrophicans [4, 5, 11, 17, 33, 63].

Neurological lesions are characterized by polyradiculoneuritis, progressive encephalomyelitis, cerebral vasculitis, and encephalopathy.

PNS lesions most frequently manifest as spinal or craniospinal radiculopathies and radiculoneuritis. The symptom complex—consisting of an acute onset of the disease with a pronounced general infectious syndrome, neck and upper extremity muscle paresis with hyporeflexia and atonia, and an inflammatory cerebrospinal fluid profile (cytological examination of cerebrospinal fluid cells, cerebrospinal fluid glucose level, and cerebrospinal fluid protein level)—may resemble the encephalopoliomyelitic manifestations of tick-borne encephalitis (TBE).

Progressive encephalomyelitis manifests as escalating signs of spinal cord and brain involvement in the form of spastic paraparesis, ataxia, pyramidal and extrapyramidal symptoms, and progressive mental disorders. Clinical manifestations may include dizziness, sleep inversion, central-type cranial nerve palsy, and asymmetry of deep reflexes and oral automatism reflexes. The progression of the inflammatory process in the central nervous system leads to a multifocal demyelinating lesion, which requires specific differential diagnosis with multiple sclerosis.

A characteristic feature of borreliosis encephalomyelitis is its combination with arthropathies, typically presenting as the arthralgic variant of musculoskeletal involvement [34].

In neuroborreliosis, significant functional disorders of cerebral circulation reliably develop, manifested by increased tone of small- and medium-sized arteries and, consequently, increased peripheral resistance, as well as impaired venous outflow, leading to suppressed blood supply to both the brain and the cortex.

There is also evidence of TBB-associated Guillain-Barré syndrome. Cases of autoimmune demyelinating polyradiculoneuropathy developing after the resolution of erythema migrans with serological confirmation of the disease have been described [35].

Mental manifestations are long-lasting and protracted in nature [36]. One striking manifestation is the so-called "Alice in Wonderland" syndrome. Micropsia is a disorienting neurological condition in which a person visually perceives surrounding objects as proportionally reduced. The patient experiences a distorted perception of the shape, size, color, rest, or movement of objects, along with auditory hallucinations [37].

Borreliosis encephalopathy is characterized by scattered focal symptoms, cerebellar disorders, asthenic syndrome, and intellectual-mnestic and cognitive deficits.

The most important clinical syndrome is musculoskeletal involvement, which manifests as persistent large joint damage—mono- or oligoarthritis running a remitting course with alternating attacks and remissions. The duration of a single attack can range from several days to a month or more. Within 2–3 years, arthritis typically becomes chronic, with the formation of marginal bone erosions, ossification of periarticular tissues, osteoporosis, contractures, and joint ankylosis. Painless swelling of the hands and feet resembling angioneurotic syndrome is also possible.

Skin manifestations of the chronic course of TBB primarily include acrodermatitis chronica atrophicans (ACA). The duration of ACA can span years, sometimes decades. In typical presentations, the extensor surfaces of the distal extremities are affected. Over years, the infiltrative-inflammatory stage transforms into the edematous and sclerotic stages of the disease. Initially, confluent cyanotic-red spots appear, resembling diffuse erythema with skin edema. Then the erythema resolves, and pronounced atrophy forms in its place, with the skin acquiring the appearance of cigarette paper. Sclerotic changes resembling scleroderma may also develop. Typically, ACA is combined with other organ manifestations characteristic of the chronic course of TBB.

The development of benign cutaneous lymphocytoma (lymphadenosis cutis) is also possible, presenting as a tumor-like induration on the earlobe or in the area of the mammary gland nipple, less commonly on other areas of the skin.

Palmar and nodular erythema are also possible in TBB.

A relatively rare clinical manifestation of TBB is eye involvement—ophthalmoborreliosis—which can feature conjunctivitis, panophthalmitis, chorioretinitis, iridocyclitis, and keratitis [38]. A case of recurrent uveitis lasting 2 years against the background of chronic TBB, successfully treated with a course of ceftriaxone**, has been described [39].

Cardiological manifestations in the chronic course of TBB are essentially similar to those in the subacute form of the disease. In rare cases, pericarditis, endocarditis, and dilated cardiomyopathy develop, the severity and prognosis of which depend on the duration of TBB [40, 64]. It is currently believed that chronic TBB is the third leading cause of dilated cardiomyopathy after viral and autoimmune diseases. The results of PCR analysis of endomyocardial samples obtained via heart biopsy in patients with dilated cardiomyopathy have proven a causal relationship between B.b.s.l. infection and the development of this symptom complex [41].

Clinical picture of mixed infection (tick-borne encephalitis and Lyme borreliosis)

The incubation period in mixed infection is somewhat shorter, averaging 10–12 days (1–35 days).

In mixed infection, febrile and inapparent forms of TBE are generally observed. The feature of the infectious process is the predominance of clinical manifestations of either TBB, TBE, or the manifestation of one disease against the background of a latent course of the other infection. In the latter case, TBE clinically manifests more frequently against the background of a latent TBB course.

Features of mixed infection include a higher frequency and severity of general infectious and neurological manifestations, as well as an increased proportion of non-erythematous forms of TBB. With the erythematous form of the disease, a mild course of mixed infection is more commonly registered.

Examples of diagnosis formulation

• Lyme disease, acute course, latent form

• Lyme disease, acute course, manifest erythematous form, moderate severity

• Lyme disease, acute course, manifest non-erythematous form, mild severity

• Lyme disease, subacute course, manifest non-erythematous form, moderate severity, with predominant cardiovascular involvement (second-degree atrioventricular block)

• Lyme disease, chronic relapsing course, with predominant musculoskeletal involvement (arthrosis-arthritis of the right knee joint), subcompensated stage

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of Lyme disease

Criteria for establishing the diagnosis/condition:

The diagnosis of Lyme disease is established based on pathognomonic data:

1) epidemiological history (history of a tick bite or arrival from an unfavorable area, stay in a forest zone of an endemic region);

2) physical examination (presence of a primary affected site, erythema migrans, lymphadenopathy, intoxication syndrome, symptoms of internal organ involvement within a month after a tick bite [41, 42]).

The clinical diagnosis can be considered reliable only in the presence of erythema migrans; in this form, Lyme disease does not require serological confirmation [25, 42, 43].

3) To make a definitive diagnosis of Lyme disease, mandatory laboratory confirmation is required.

• All patients with suspected Lyme disease are recommended to undergo ELISA testing for IgM antibodies to Borrelia burgdorferi (from the 2nd week of illness) and detection of a rising titer of IgG antibodies to Borrelia burgdorferi (from the 4th week) in paired sera (with an interval of 20 days). For patients in the dissemination and persistence stages, to confirm the specificity of antibody detection results in ELISA, it is recommended to determine IgM and IgG antibodies to individual Borrelia antigens using immunoblotting. Detection of Borrelia DNA by PCR in biological material (cerebrospinal fluid, synovial fluid) is indicated for corresponding syndromes (meningoencephalitis, arthritis) [66, 67].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

The diagnosis of Lyme neuroborreliosis is based on the criteria of the European Federation of Neurological Societies [33].

"Probable" neuroborreliosis is established if the patient presents with 1 characteristic clinical and 1 laboratory parameter.

"Definite" neuroborreliosis is established if the patient presents with 1 clinical and 2 laboratory parameters (pleocytosis and intrathecal production of specific antibodies to B. burgdorferi).

The diagnosis of Lyme disease is made on the basis of epidemiological and clinical history, clinical examination, laboratory and special diagnostic methods, and is aimed at identifying the nosology and clinical form, severity of the condition, complications, and indications for therapy.

2.1 Complaints and Anamnesis

Comment: the absence of a history of a tick bite or staying in park and forest areas during the epidemic season for tick-borne infections does not rule out the development of the disease, since the tick bite may go unnoticed, and ticks may also migrate from forest areas into urban limits. Borrelia infection may manifest without an acute period, as well as months or even years later, so the seasonality of the onset of the first clinical signs in these cases is of no practical significance.

2.2 Physical Examination

Comments: the presence of EM for the diagnosis of the erythematous form of Lyme disease does not require serological confirmation, since borrelia infection is characterized by delayed antibody genesis. Therefore, the diagnosis of the erythematous form of the disease is established on the basis of clinical and epidemiological data. It is necessary to assess the skin for the presence of EM as a pathognomonic clinical manifestation of the acute course of the erythematous form of the disease associated with the tick bite site, and secondary multiple erythemas. Attention should be paid to the presence of cerebral and/or focal symptoms, meningeal signs (nuchal rigidity, Kernig's, Brudzinski's, Bekhterev's signs, etc.), asymmetric paresis of peripheral and cranial nerves, somnolence or psychomotor agitation for the diagnosis of neuroborreliosis, its severity, and the course of the disease. The severity of cerebral injury correlates with the Glasgow Coma Scale score. Glasgow Coma Scale (GCS) is an internationally recognized tool for the objective assessment of the level of consciousness in patients with CNS infections. Scores on the scale allow tracking the dynamics of the patient's condition and making decisions regarding the need for intubation, neuroimaging, or transfer to the ICU (Appendix G4 ).

Comments: the level of consciousness is assessed using the Glasgow Coma Scale (Appendix G4), along with the extent of CNS and PNS involvement. Attention should be paid to the presence of meningeal and focal signs indicating the development of meningitis and/or meningoencephalitis, respectively, radiculalgia, monoparesis of cranial nerves (most commonly facial or abducens), peripheral nerves, and Bannwarth syndrome, which is characterized by a combination of lymphocytic meningitis, facial nerve palsy, and radiculoneuritis, and serves as a pathognomonic clinical manifestation of neuroborreliosis.

Comments: consideration should be given to the presence of cardialgia, cardiac arrhythmias (bradycardia or tachycardia, extrasystoles), and cardiac conduction disturbances (first- or second-degree AV block, intraventricular block, bundle branch blocks, complete transverse heart block, delayed impulse propagation through the cardiac conduction system [prolonged PQ, QRS], delayed left ventricular repolarization [prolonged QT interval], early diastolic myocardial dysfunction, as well as inflammatory myocardial phenomena and impaired myocardial contractility).

Comment: musculoskeletal involvement in the form of mono- or oligoarthritis and/or arthrosis is more frequently observed in the chronic course of the disease, often combined with other organ lesions, and tends to be recurrent. While pain syndrome is clinically present, the inflammatory component should be established using instrumental diagnostic methods, in particular, ultrasound, MRI, and/or radiography of the joints.

2.3 Laboratory Diagnostics

2.3.1. Nonspecific laboratory diagnostics

Comments: moderate leukocytosis and an elevated ESR are possible in Lyme disease.

2.3.2. Specific laboratory diagnostics

Comments: since borrelia infection is characterized by a slow antibody response, serological test results in the early stages of the infectious process may yield false negatives; therefore, if the result is negative, it is necessary to test blood serum for specific antibodies dynamically during the course of the disease, specifically at 3 weeks, 6 weeks, 3 months, and 6 months.

Comments: for the differential diagnosis of chronic borreliosis from symptom-similar diseases, all patients should undergo immunoblotting (determination of antibodies to pathogens of Ixodes tick-borne borreliosis of the Borrelia burgdorferi sensu lato group in the blood), which makes it possible to detect specific antibodies to certain borrelial proteins encoded by chromosomal genes: p83-100, p73, p66, p58, p41, p39 (BmpA), as well as plasmid genes: OspA, OspC (p20-25), OspB, p17, p31, BBK32, VlsE. When determining IgM antibodies by immunoblotting, the result is considered positive if antibodies are detected against the OspC protein and at least two antigens from the group: VlsE, p41, p39, p17. When determining IgG antibodies by immunoblotting, the result is considered positive if antibodies are detected against VlsE (a highly recombinant purified antigen) and 4 antigens from the group: p83-100, p19, p21, p23, p28, p30, p39, p41, p45, p58, p66.

Comment: the PCR method is highly sensitive and theoretically allows the detection of a few single DNA molecules in biological material. However, currently, only the genetic structure of strain B31 (B.b.s.s.), which is the reference strain for the entire group of tick-borne borreliosis pathogens, is fully known. The genetic structure of identical loci across different borrelia genospecies exhibits heterogeneity, which often leads to false-negative results. PCR has the highest diagnostic value for detecting borrelia in the blood 7–14 days after a bite from a borrelia-infected tick due to spirochetemia, as well as in CSF PCR when neuroborreliosis with CNS involvement is suspected.

We believe that determining the DNA of pathogens of Ixodes tick-borne borreliosis of the Borrelia burgdorferi sensu lato group in skin biopsy specimens by PCR to verify the erythematous form of the disease is not justified in clinical practice, since diagnosing the erythematous form does not present difficulties. However, for differential diagnosis to confirm the borrelial etiology of acrodermatitis chronica atrophicans in the chronic course of the disease, the efficacy of molecular genetic testing of skin biopsies is 60–61% [49, 50]. Furthermore, determining the DNA of pathogens of Ixodes tick-borne borreliosis of the Borrelia burgdorferi sensu lato group in synovial fluid by PCR is also unjustified, as the pathogen is known to localize in the border layers of the synovium [44, 45].

2.3.3 Special laboratory diagnostics

Comments: the general routine biochemical blood test does not provide any specific information, but the detected abnormalities have certain prognostic significance and influence the choice of medications and/or their dosing regimen.

2.4 Instrumental Diagnostics

Comment: lumbar puncture is performed within the first 24 hours of establishing a probable diagnosis of neuroborreliosis. In Lyme disease with CNS involvement, lymphocytic pleocytosis, a slight increase in protein, and normal glucose levels are typically observed; in meningoencephalitis, protein-cytologic dissociation is observed.

Lumbar puncture can only be performed in the absence of contraindications; if present, the procedure is carried out after the patient's condition has stabilized and cerebral edema has been managed.

Comments: first- to third-degree atrioventricular blocks, extrasystoles, and other rhythm and cardiac conduction disorders are characteristic of cardiac involvement in Lyme borreliosis. Serial ECG monitoring is mandatory. If atrioventricular block is detected, serial ECG monitoring is indicated throughout the entire course of antibacterial therapy.

Comments: echocardiography may reveal impaired cardiac contractility, and very rarely, heart valve insufficiency, chamber dilation, or diffuse weakness of the heart muscle.

Comments: EEG changes are non-specific. In meningitis, occasional bursts of delta and theta waves may occur, which increase with hyperventilation loading. In encephalitis, slow-wave activity in the delta-theta range interspersed with irregular alpha waves is observed. EEG changes allow for the adjustment of pathogenetic therapy.

Comments: Brain MRI in neuroborreliosis is characterized by the appearance of hyperintense signals on T2-weighted images and FLAIR sequences in the cerebral white matter. The pathological process may also involve the brainstem and cerebellum.

Comments: against the background of preserved motor-sensory nerve conduction velocity, conduction blocks and decreased excitability of peripheral nerves are determined. F-waves may be absent with asymmetry in nerve recording at slightly increased latencies of these waves. In multiple neuropathies, decreases in the amplitudes of sensory nerve potentials are detected.

2.5 Other Procedures

Differential diagnosis of Lyme disease

Differential diagnosis is carried out with tick-borne diseases, other spirochetoses, and diseases characterized by infectious and non-infectious multiorgan and systemic lesions of the skin, musculoskeletal system, cardiovascular, and nervous systems.

The spectrum of diseases differentiated from Lyme disease in the subacute and chronic periods of the disease is extremely wide. This is due to the polymorphism of the clinical symptoms of Lyme disease.

At the fourth stage, differential diagnosis is performed with other general somatic diseases, including those of infectious origin, accompanied by syndromes of musculoskeletal, cardiovascular, and nervous system lesions based on the results of two-tier serological diagnostics (ELISA, immunoblotting) [40].

Comments: if any tick-borne infection is suspected, the spectrum of laboratory diagnostics should be expanded as much as possible, taking into account the epidemiological situation in the region where the tick bite occurred. Differential diagnosis of Lyme disease with other tick-borne infections is presented in Appendix G3.

Comments: the similarity of antigenic structures of Borrelia and Treponema pallidum can cause false-positive or false-negative results in serological diagnostics with specific diagnostic kits for syphilis; therefore, it is advisable to perform serological diagnostics between these diseases using more sensitive and specific methods—determination of antibodies to Treponema pallidum by enzyme-linked immunosorbent assay (ELISA) in the blood. The diagnosis of leptospirosis is confirmed by the determination of antibodies to Leptospira interrogans in the blood (Appendix G4).

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

General approaches to treatment

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 Lyme disease provide for the simultaneous resolution of several tasks: prevention of the further development of the pathological process caused by the disease; prevention of the development and relief of pathological processes of complications; prevention of the formation of residual effects, relapsing, and chronic courses.

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;

- availability and feasibility of treatment in accordance with the required type of medical care [4].

The method of treatment for Lyme disease is determined depending on the clinical picture, degree of symptom manifestations, severity of the disease, and presence of complications.

Conservative treatment includes drug therapy methods: etiotropic therapy agents; pathogenetic treatment agents; symptomatic therapy agents [3].

Comments: hospitalization of patients is due to the high risks of developing combined infection, the rapid dissemination with organ involvement (especially the nervous system and heart), the need for parenteral administration of antibiotics, and a wide range of laboratory and instrumental diagnostics.

3.1 Regimen, diet

Comments: duration of bed rest in severe cases: 2–3 weeks. No special diet for the underlying disease is required (general hospital diet). Nutritional correction should be carried out taking into account the presence/absence of concomitant pathology and the integrity of the swallowing act.

3.2. Conservative treatment

Etiotropic treatment.

Comments: patients with stage 1 LB are prescribed oral systemic antibacterial drugs for 10-14 days. In stage II of the disease, depending on the localization of the process, etiotropic drugs are prescribed per os or parenterally for 14-21 days. In stage III, the parenteral route of administration is preferred for a duration of 21-28 days; if necessary, the course of antibacterial therapy is repeated.

Comments: Cefuroxime**, Cefotaxime**, and Ceftriaxone** are used. In stage I of the disease, Cefuroxime** (film-coated tablets) 500 mg twice daily per os is prescribed for 10-14 days. The prescription of 3rd generation cephalosporins is preferred over 2nd generation in neuroborreliosis due to better penetration through the blood-brain barrier. In stage II of the disease with the development of meningitis or carditis, Cefotaxime** 2 g/day in 2 divided doses or Ceftriaxone** at a dose of 2 g/day once intravenously is used for 14-21 days. In stage III LB with involvement of the nervous system (meningitis, encephalitis, poliomyelitis, cranial neuropathy, radiculoneuropathy), heart (carditis, atrioventricular block), and musculoskeletal system (arthritis), Ceftriaxone** is prescribed at a dose of 2 g/day once intravenously for 21-28 days.

Comments: Doxycycline** is the drug of choice, prescribed in stage I of the disease at 100 mg twice daily per os for a course of 10-14 days. In stage II of the disease with involvement of the peripheral nervous system and skin (lymphocytoma cutis), Doxycycline** is used at a dose of 100 mg twice daily per os for 14-21 days. For skin manifestations of stage III of the disease (acrodermatitis chronica atrophicans, lymphocytoma cutis) and initial arthritis treatment, Doxycycline** is prescribed at 100 mg twice daily per os for 21-28 days.

Comments: Amoxicillin** or #Amoxicillin + [Clavulanic acid] 1,000 mg 3 times daily per os is used for 10-14 days in stage I of the disease, and 14-21 days in stage II.

Comments: Azithromycin** is used, prescribed once daily per os for 5 days: day 1 - 1000 mg, then from days 2 to 5 - 500 mg each (total course dose 3.0 g).

Pathogenetic therapy

Comments: for the treatment of chronic LB with late neuroborreliosis syndromes such as leukoencephalitis, leukoencephalomyelitis, encephalomyelopolyradiculoneuritis, dexamethasone** is used at a daily dose of 12-16 mg IV drip once a day for 3-5 days.

Comments: NSAIDs are prescribed for neuroborreliosis presenting as multiple, monospinal, or cranial neuropathy syndromes, radiculopathies, neuropathies, in patients with encephalomyelitis or myelitis, arthralgia, and Lyme arthritis when pain is present.

3.3 Surgical Treatment

Surgical treatment is not performed.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: medical rehabilitation for all patients who have suffered LB should be carried out in state healthcare medical organizations or their respective structural subdivisions, including centers for reconstructive medicine and rehabilitation, as well as spa and resort treatment within the respective profile. The following basic principles must be observed during rehabilitation:

- rehabilitation measures should begin already in the peak period or in the early convalescence period;

- it is necessary to maintain the consistency and continuity of the measures carried out, ensuring continuity at various stages of rehabilitation and follow-up (dispensary observation);

- a comprehensive nature of recovery measures involving various specialists and using a variety of intervention methods;

- adequacy of rehabilitation and recovery measures and interventions to the adaptive and reserve capabilities of the convalescent. At the same time, it is important to gradually increase dosed physical and mental loads, as well as use differentiated methods of intervention;

- constant monitoring of the effectiveness of ongoing measures. This takes into account the speed and degree of restoration of the functional state and occupationally significant functions of convalescents (using indirect and direct methods).

5. Prevention and Dispensary Observation

General approaches to prevention.

LB prevention consists of specific and non-specific protection measures.

5.1 Specific prophylaxis of Lyme borreliosis

Vaccine prophylaxis for LB is currently unavailable.

An indication for emergency prophylaxis is the fact of a tick bite and the results of parasitological and microbiological studies—detection of Borrelia in the attached tick by PCR or dark-field microscopy. All patients who have suffered a tick bite should be prescribed antibiotic prophylaxis for LB as early as possible after its discovery to prevent the development of infection. Preventive antibiotic therapy must be initiated no later than 5 days from the moment of the tick bite, most effectively starting from the first day, which reliably reduces the risk of developing LB [3, 4, 5, 61].

Comments: the use of systemic antibacterial drugs in the first 72 hours from the moment of the tick bite reliably reduces the risk of developing Lyme disease. The following are recommended for emergency antibiotic prophylaxis:

- #Doxycycline** 0.1 g 2 times a day orally for 5 days. When prescribing #doxycycline** in the form of monohydrate (hydrochloride) after the 5th day from the moment of the tick bite, the course of administration is extended to up to 10 days. The possibility of developing photosensitization when taking #doxycycline** in the summer should be considered [4, 5, 17, 70, 74, 75, 76, 79];

- a prolonged beta-lactamase-susceptible penicillin — #benzathine benzylpenicillin + Benzylpenicillin procaine — 1.5 million IU, course: single dose [5, 74, 75, 76, 79];

- #Amoxicillin** — 0.5 g 3 times a day, course: 5 days; #amoxicillin [Clavulanic acid]** — 0.325 g 3 times a day, course: 5 days [5, 74, 75, 76, 79].

GRL CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) Level C (Level of Evidence – 5).

5.2 Nonspecific prophylaxis of Lyme borreliosis

Non-specific prevention measures include protection against tick bites and/or their eradication:

1) Organization of control measures against ticks as vectors of infections. To this end, epidemiological services organize and conduct scheduled acaricidal treatments of areas in health resort facilities, recreation areas, tourism sites, parks, and territories of gardening and horticultural cooperatives.

2) Use repellents containing DEET or permethrin approved for use in children. Repellents are applied to the skin or clothing (according to the instructions) [3, 56, 57, 58].

3) Avoid visiting tick habitats (forest biotopes with tall grass, shrubs) in May–June; stick to paths during hikes; wear clothing with long sleeves and trousers, preferably tucking trouser legs into long socks. Hair should be tucked under a headwear. To make ticks easier to spot, it is preferable to wear light-colored clothing; regular inspection of clothing is recommended while in the forest; upon returning from the forest, inspect clothing and the body. Since some areas of the body are inaccessible to self-examination, ask friends or family to check the back and scalp. Tick larvae are very small and may go unnoticed on clothing. To prevent them from attaching, it is recommended to wash clothing in hot water [3, 56, 57, 58]. The effectiveness of preventive measures using protective clothing against Lyme disease was 40%.

4) Conduct health education and awareness activities among the population.

5) If an attached tick is found, it should be removed immediately. The earlier the tick is removed, the lower the likelihood of infection. The tick can be removed using manicure tweezers or a thread tied around the parasite's mouthparts. The tick is removed with rocking and twisting motions. Crushing the tick must be avoided [4, 5, 7].

5.3 Dispensary follow-up

Follow-up dispensary observation of all Lyme disease convalescents, regardless of clinical form, is carried out by an infectious disease specialist, neurologist, or general practitioner (family doctor). In the event of Lyme carditis and/or Lyme arthritis, observation is carried out by a cardiologist. When indicated, consultations with subspecialists and additional instrumental and laboratory examination methods are performed. Dispensary observation aims not only at managing potential complaints and residual deficits, but also at preventing recurrences of Lyme disease [3].

In the absence of organ involvement, dispensary follow-up is performed 1 month after the end of treatment, then at 3, 6, and 12 months, mandatory with control of seroconversion (determination of class M antibodies (IgM) to tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood, determination of class G antibodies (IgG) to tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood by ELISA). The duration of observation ranges from 2 years to transfer to the adult medical network (in chronic courses). The dispensary observation schedule depending on the stage and clinical syndrome is presented in Table 1 [3].

The grounds for discharging a patient from dispensary register shall be complete recovery of working capacity, satisfactory well-being, absence of clinical signs of the disease, and positive seroconversion [3].

6. Organization of Medical Care

Medical care for patients with Lyme disease is provided in the following forms:

- primary health care;

- emergency medical care, including specialized emergency medical care;

- specialized medical care, including high-tech medical care.

Medical care for patients with suspected Lyme disease is provided in the following settings:

- inpatient (in settings providing round-the-clock medical observation and treatment).

Primary health care includes:

- primary pre-medical health care;

- primary medical health care;

- primary specialized health care.

Primary health care is provided in outpatient settings. Primary pre-medical health care in outpatient settings is provided at feldsher-midwife stations by mid-level medical personnel.

If a physician is available in these institutions, medical care is provided in the form of primary medical health care.

Primary specialized health care is provided by an infectious disease physician of a medical organization providing outpatient medical care (polyclinic).

When Lyme disease is suspected or detected at the outpatient stage, the district general practitioner (general practitioners [family doctors], infectious disease physician, mid-level medical workers of medical organizations) refers the patient for hospitalization to a hospital for specialized medical care. Referral for inpatient treatment for suspected Lyme borreliosis is issued within no more than 24 hours from the moment of the initial medical examination.

Specialized medical care for patients with Lyme disease is provided in an inpatient setting by infectious disease physicians and other medical specialists and includes the prevention, diagnosis, and treatment of diseases and conditions requiring special methods and complex medical technologies.

Treatment of Lyme disease is carried out in an inpatient setting upon referral by the district general practitioner, infectious disease physician, or general practitioner (family doctor).

7. Additional Information

Risk stratification:

In the absence of a course of antibacterial therapy in patients with manifest and latent forms of Lyme disease in the early stages of the disease, there is a high risk of a chronic course, development of neurological, cardiac, and articular lesions within 3–12 months from the moment of patient infection.

Criteria for recovery:

- persistent normalization of body temperature;

- absence of intoxication;

- normalization or significant reduction of neurological deficit, manifestations of cardiovascular system insufficiency, musculoskeletal system disorders, and relief of skin manifestations.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Bondarenko A.L. - MD, Professor, Head of the Department of Infectious Diseases, Kirov State Medical University

2. Gorelov A.V. - Academician of the Russian Academy of Sciences, Professor, Deputy Director for Research, Central Research Institute of Epidemiology of Rospotrebnadzor, Head of the Department of Infectious Diseases and Epidemiology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health

3. Konkova-Reidman A.B. - MD, Associate Professor, Head of the Department of Infectious Diseases, South Ural State Medical University of the Ministry of Health of the Russian Federation

4. Minoranskaya N.S. - MD, Associate Professor, Professor of the Department of Infectious Diseases and Epidemiology with a Postgraduate Training Course, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University of the Russian Ministry of Health

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

6. Ter-Bagdasaryan L.V. - PhD in Medicine, Associate Professor, Department of Infectious Diseases, South Ural State Medical University of the Ministry of Health of the Russian Federation

7. Uskov A.N. - Head of the Department for the Organization of Adult Medical Care, Federal Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency of Russia, MD, Associate Professor

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

9. Chernykh V.I. - Assistant at the Department of Infectious Diseases and Epidemiology with a Postgraduate Training Course, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University of the Russian Ministry of Health, Head of Infectious Diseases Department No. 1, Krasnoyarsk Interdistrict Clinical Emergency Hospital named after N.S. Karpovich

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

11. Esaulenko E.V. - MD, Professor, Head of the Department of Adult Infectious Diseases and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health

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

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Infectious diseases physicians;

2. General practitioners;

3. General practitioners (family physicians).

Table P1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table P2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (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

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on July 2, 2021) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724) (with amendments and additions, effective from October 1, 2021) (https://roszdravnadzor.gov.ru/documents/100);

2. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of the Criteria for Evaluating the Quality of Medical Care" (Registered with the Ministry of Justice of Russia on May 17, 2017, No. 46740) (http://publication.pravo.gov.ru/Document/View/0001201705170016?rangeSize=1);

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

5. Federal Law of the Russian Federation No. 52-FZ dated March 30, 1999, "On the Sanitary and Epidemiological Welfare of the Population" (as amended on July 13, 2020);

6. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services", registered with the Ministry of Justice on November 7, 2017, Registration No. 48808 (as amended on March 24, 2020);

7. Order of the Ministry of Health and Social Development of Russia No. 541n dated July 23, 2010, "批准" ["On Approval of the Unified Qualification Handbook of Positions of Managers, Specialists, and Employees"], section "Qualification Characteristics of Employee Positions in Healthcare", registered with the Ministry of Justice of the RF on August 25, 2010, Registration No. 18247 (as amended on April 9, 2018);

8. Order of the Ministry of Health of the Russian Federation No. 302n dated May 16, 2019 (as amended on November 19, 2020) "On Approval of the Procedure for Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations" (Registered with the Ministry of Justice of Russia on June 7, 2019, No. 54887) (https://docs.cntd.ru/document/554715762);

9. International Classification of Diseases, Injuries and Causes of Death (ICD-10) (https://mkb-10.com/);

10. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On 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...") (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500);

11. Methodological Guidelines MU 3.5.3011-12 "Nonspecific Prevention of Tick-Borne Viral Encephalitis and Ixodes Tick-Borne Borrelioses (approved by the Chief State Sanitary Doctor of the RF on April 4, 2012) (https://docs.cntd.ru/document/1200095239);

12. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 (as amended on May 25, 2022) On 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) (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500);

13. Order of the Ministry of Health of the Russian Federation No. 302n dated May 16, 2019, "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations" (with amendments and additions) (https://base.garant.ru/72265358/);

15. Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On Approval of the National Immunization Schedule and the Immunization Schedule for Epidemiological Indications" (https://docs.cntd.ru/document/727605537);

16. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of the Criteria for Evaluating the Quality of Medical Care" (https://docs.cntd.ru/document/436733768);

17. State Register of Medicines (http://www.grls.rosminzdrav.ru/grls.aspx);

18. Therapeutic Nutrition Standards. Methodological Guide. 2017. Access: http://cr.rosminzdrav.ru/#!/manuals/adults//

19. International Classification of Diseases, Injuries and Causes of Death (ICD-11) (https://mkb-11.com/);

20. Order No. 1010n dated September 24, 2020, "On Amendments to Section II 'Nomenclature of Medical Services' of the Nomenclature of Medical Services", approved by Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 (https://normativ.kontur.ru/document?moduleId=1&documentId=378890).

Stages of serological diagnosis of Lyme borreliosis [3, 7, 23, 25, 34, 36, 37]

Differential diagnosis of Lyme borreliosis from other tick-borne diseases

Differential diagnosis of Lyme borreliosis from other spirochetoses

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Lyme borreliosis is an infectious disease caused by a specific type of bacteria — Borrelia. The disease is widespread in various parts of the globe; in the territory of the Russian Federation, LB is the most frequent tick-borne disease. The disease is characterized by spring-summer seasonality, although cases also occur in autumn (September–October). As a rule, tick bites occur in rural areas, when visiting forests and forest parks. Ticks may be brought into homes on the fur of pets, items of clothing, flowers, or other things brought from the forest. In such cases, the tick may attach a few days after a person leaves the endemic focus. Human infection with Borrelia occurs predominantly as a result of a female tick bite. In adults, the tick attaches most often in the neck, chest, axillary, and inguinal folds areas, i.e., in areas with thin skin and abundant blood supply. In children, the most frequent attachment site is the scalp and retroauricular areas. Unfortunately, in a number of cases, the fact of a tick bite may go unnoticed (especially in cases of male tick bites), which leads to an underestimation of subsequent symptoms and late diagnosis of LB.

Symptoms of Lyme Disease.

Clinical symptoms of LB are diverse; however, skin manifestations are the most characteristic of the disease. Typical for LB is the appearance of annular erythema, which can occur from a few days to 30 days after the tick bite and is most often localized in the bite area. Initial manifestations of annular erythema look like a red spot that centrifugally increases in size with central clearing or is of a homogeneous appearance (without central clearing) with a diameter from 2 to 70 cm. In some cases, skin manifestations of LB may appear as multiple annular erthyemas or other rashes varying in shape and size.

Non-specific symptoms of LB in the early stages of the disease include:

- fever;

- chills;

- headache;

- fatigue;

- muscle and joint pain;

- sleep disturbance.

In some cases, involvement of the cardiac and/or nervous system is possible as early as in the early stages of the disease, with the addition of corresponding symptoms:

- cardiac rhythm disorders;

- impaired movement of facial expression muscles;

- appearance of meningeal symptoms.

If left untreated, LB can become systemic. Symptoms of late-stage LB include arthritis (painful, swollen joints) and various problems related to nervous system involvement.

Prevention of Lyme Borreliosis

The main preventive measure is the prevention of tick bites, for which the following rules must be followed:

1. Use repellents in accordance with their instructions to help prevent tick attacks.

2. When visiting forests, grassy thickets, and shrubs, wear light-colored clothing with long sleeves and pant legs, tuck pant legs into socks or boots for additional protection. Regularly inspect (self-inspection/peer inspection) for ticks when staying in infected areas.

3. If an attached tick is found, remove it as quickly as possible. Use tick tweezers (or other pointed tweezers), grasp the tick's body as close to the skin as possible, with gentle counterclockwise turns in a steady upward direction, make careful movements until the tick comes out. Place the tick in a sealed container for subsequent testing for possible transmitted infections. Apply an antiseptic to the bite area, wash your hands with soap.

4. After the tick is removed, consult a doctor and report the tick bite. Subsequent management tactics should be determined by the doctor after an objective examination and obtaining data from the tick testing.

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

Original Name. Glasgow Coma Scale (GCS)

Source: https://www.glasgowcomascale.org/

Type: scale

Purpose: intended to assess the degree of impaired consciousness and coma. The scale consists of three tests evaluating eye-opening, verbal, and motor responses. A specific number of points is awarded for each test.

Interpretation of results:

15 points — clear consciousness;

14–13 points — moderate stupor;

12–11 points — deep stupor;

10–8 points — sopor;

7–6 points — moderate coma;

5–4 points — deep coma;

3 points — beyond coma, brain death.