Lyme disease, Lyme borreliosis: symptoms and treatment

Lyme disease, or Lyme borreliosis, is a bacterial infection transmitted to humans by the bite of infected ticks of the genus Ixodes. The causative organisms belong to the Borrelia burgdorferi sensu lato complex and vary in prevalence by region: in North America, Borrelia burgdorferi sensu stricto is most common, while in Europe, Borrelia afzelii and Borrelia garinii predominate. The disease progresses in stages, affecting the skin, nervous system, heart, and joints, and is completely curable in most patients with early treatment. [1]

Transmission of infection occurs when a tick attaches for hours and often days; the risk increases significantly after prolonged feeding. Prompt tick removal and observation during the first few weeks can reduce the risk and promptly recognize characteristic signs, such as erythema migrans. [2]

Early clinical diagnosis relies on recognition of the typical skin rash and the epidemiological context. Laboratory confirmation is typically performed using two-step serological algorithms, standard or modified, taking into account the timing of antibody production. Correct interpretation of results is important to avoid both overdiagnosis and underdiagnosis. [3]

In the early stages, short courses of antibiotics lead to rapid recovery; for nervous system or cardiac lesions, different regimens and sometimes intravenous administration are required. Long or repeated courses without indications do not increase effectiveness and may cause harm. [4]

Code according to ICD 10 and ICD 11

The International Classification of Diseases, Tenth Revision, uses code A69.2 for Lyme disease. This code covers the main clinical manifestations of the disease, including erythema migrans and late complications. The use of this code helps standardize registration, reporting, and insurance statistics. [5]

The International Classification of Diseases, Eleventh Revision, uses block 1C1G for Lyme borreliosis, with clarified entries for localized and disseminated infections. The transition to the Eleventh Revision allows for more precise coding of organ forms and stages, which is important for clinical practice, surveillance, and research. [6]

Table 1. International Classification of Diseases codes for Lyme disease

Classifier	Code	Description
ICD-10	A69.2	Lyme disease
ICD-11	1C1G	Lyme borreliosis, with subcategories for localized and disseminated forms

Epidemiology

In the United States, over 89,000 cases were registered in 2023 according to national surveillance. At the same time, according to insurance claims analysis, the annual number of diagnosed and treated cases reaches approximately 476,000, reflecting significant hidden morbidity and accountability. [7]

The sharp increase in official reports in 2022 to approximately 63,000 cases is explained by a change in case definition and simplification of criteria in high-incidence states; this improved detection in surveillance and did not necessarily indicate a real jump in risk. Geography remains stable, with the highest burden in the northeastern and midwestern states. [8]

In Europe, Lyme disease is the most common tick-borne infection in temperate climates. Systematic reviews show significant intercountry variability in incidence, reaching high levels in certain regions of Central and Northern Europe, with a trend toward expansion. [9]

Key population-level risk factors include tick and reservoir host density, landscape changes, and climate trends that extend the season and range of tick activity. This influences seasonality: peak activity occurs during the warmer months, when nymphs, often unnoticeable to humans, are active. [10]

Reasons

The causative agent is a spirochete of the Borrelia burgdorferi sensu lato complex, transmitted by the bite of ixodid ticks. In North America, Borrelia burgdorferi sensu stricto is clinically significant; in Europe, Borrelia afzelii and Borrelia garinii predominate, which is reflected in the characteristics of the clinical manifestations. [11]

The vectors vary by region: Ixodes scapularis and Ixodes pacificus in North America, and Ixodes ricinus and Ixodes persulcatus in Europe. Human infection occurs when an infected tick feeds long enough for the bacteria to migrate from the tick's gut into the blood.[12]

Borrelia mayonii, which can cause more severe bacteremia and sometimes different clinical manifestations, has been detected in certain regions of North America, but is less common. This information is important for laboratory diagnostics and the selection of test systems. [13]

The association of genospecies with organotropism partly explains European cutaneous forms such as borrelia lymphocytoma and acrodermatitis chronica atrophicans, which are more often associated with Borrelia afzelii, whereas Borrelia garinii is more often associated with neurological manifestations.[14]

Risk factors

Individual risk factors include exposure to forest and meadow habitats during tick season, tourism and hunting, working outdoors, and living in endemic areas. Wearing revealing clothing, not using repellents, and failing to inspect the skin promptly increase the likelihood of being bitten. [15]

The risk of transmission depends on the duration of the tick's attachment and the degree of its blood supply. Prompt removal within the first 24 hours significantly reduces the risk of infection, although rare exceptions are possible, so monitoring for symptoms remains essential. [16]

Children and adolescents are at higher risk of being bitten due to their active outdoor activities. Dog and cat owners are also at risk, as pets can bring ticks into the home even if they are not sick or transmitting the infection directly. [17]

Coinfections transmitted by the same ticks, such as anaplasmosis and babesiosis, increase clinical severity and complicate diagnosis, particularly in cases of fever unresponsive to doxycycline therapy. Coinfections are critical in cases of prolonged fever and hemolysis. [18]

Pathogenesis

After inoculation with tick saliva, the spirochetes adapt to host tissues, switching the expression of surface proteins and evading the immune response. The early stage is limited to the skin, with the formation of erythema migrans; hematogenous dissemination and colonization of the nervous system, heart, and joints are then possible. [19]

The immune response involves innate and adaptive mechanisms, with the production of antibodies to various Borrelia antigens. Serological tests detect these antibodies, but their production takes time, which explains the negative results early on. [20]

Regional gene specificities partially determine tissue targets: cutaneous late forms in Europe are more often associated with Borrelia afzelii, whereas neurotropic forms are more often associated with Borrelia garinii. This organotropic nature is reflected in the clinical spectrum of European Lyme borreliosis. [21]

Late manifestations, such as chronic acrodermatitis and arthritis, are caused by persistent antigens and immune mechanisms. However, prolonged antibiotic therapy beyond the standard does not accelerate the resolution of immune complications and may increase harm. [22]

Symptoms

The early localized stage typically presents with erythema migrans—an expanding spot at the bite site, partly with a central clearing. General symptoms are common: malaise, low-grade fever, myalgia, and headache. Diagnosis at this stage is primarily clinical, without waiting for tests. [23]

The early disseminated stage includes multiple erythemas, aseptic meningitis, radiculoneuritis, facial nerve paresis, neurosensory complaints, as well as myocarditis and atrioventricular blocks of varying degrees. Migrating pain in the joints and tendons may be observed. [24]

The late stage is characterized by inflammatory arthritis of large joints, most often the knee, with a recurrent course. In Europe, late cutaneous manifestations are possible, including chronic atrophic acrodermatitis and borreliosis lymphocytoma. [25]

Some patients experience persistent fatigue, pain, and cognitive complaints after treatment. These post-infectious symptoms do not indicate an ongoing infection, and additional antibiotic therapy is not indicated; supportive and rehabilitative approaches are used. [26]

Classification, forms and stages

Classically, three stages are distinguished: early localized, early disseminated, and late. This division helps correlate clinical presentation, diagnostic tactics, and treatment options with the duration and prevalence of the infection. [27]

Cutaneous forms include erythema migrans, borreliosis lymphocytoma, and acrodermatitis chronica atrophicans. The latter is characteristic of Europe, has a long course, and requires caution and confirmation by serology and biopsy. [28]

Neurological manifestations include meningitis, radiculoneuritis, and facial nerve palsy; in cases of parenchymal brain or spinal cord involvement, consultation with a neurologist and specialized therapy are necessary. Cardiac manifestations range from mild conduction disturbances to high degrees of block. [29]

Lyme arthritis is characterized by paroxysmal pain and swelling of one or more large joints, with potential relapses after initial treatment. If there is no response to the first course, alternative regimens may be needed as recommended. [30]

Table 2. Stages and most common manifestations

Stage	Leather	Nervous system	Heart	Joints
Early localized	Erythema migrans	No	No	Algia without arthritis
Early disseminated	Multiple erythema	Meningitis, radiculoneuritis, facial nerve paresis	Blockade, myocarditis	Arthralgia
Late	Chronic acrodermatitis, lymphocytoma	Polyneuropathy	Rarely	Arthritis, most often of the knee

Complications and consequences

Without treatment, the risk of nervous system damage with prolonged pain, sensory disturbances, and paresis increases. Timely diagnosis and the correct choice of antibiotics minimize neurological consequences. [31]

Cardiac complications include conduction disturbances, which may require temporary cardiac pacing in the acute phase, but in most cases are reversible with antibacterial therapy. [32]

Joint manifestations sometimes progress to protracted or recurrent inflammation. With adequate therapy, the prognosis is favorable; however, longer-term observation and anti-inflammatory support may be required. [33]

Some patients experience post-treatment symptoms after completion of treatment for which repeat courses of antibiotics are not indicated; rehabilitation, pain management, and cognitive-behavioral strategies are used. [34]

When to see a doctor

A rapidly expanding rash, particularly with central clearing, occurring within 3-30 days after a tick bite, regardless of bite recollection, requires urgent evaluation. Early treatment improves outcomes.[35]

Seek immediate medical attention if you experience symptoms of neurological deficits, including facial asymmetry, severe headache, radicular pain, difficulty walking, or numbness in the extremities. These signs require evaluation for neuroborreliosis. [36]

Seek immediate medical attention if you experience palpitations, fainting, shortness of breath, or chest pain in the setting of a recent tick bite or erythema migrans, as this may indicate Lyme carditis. Hospitalization and monitoring may be necessary.[37]

A follow-up consultation is necessary if fever persists for more than 1 day during doxycycline therapy, which raises concerns about a co-infection, such as anaplasmosis or babesiosis, and requires additional diagnostics. [38]

Diagnostics

Step 1. Clinical recognition. In typical erythema migrans, the diagnosis is made clinically and treatment is initiated without waiting for laboratory confirmation. This prevents delays in therapy, given the low sensitivity of serology in the earliest stages. [39]

Step 2. Serological confirmation for other forms. Two-step algorithms are used: a standard two-step test with immunoblot or a modified two-step test with two enzyme-linked immunosorbent assays. Both approaches are recognized and have regulatory approval when using validated test pairs. [40]

Step 3. Correct interpretation. A false-negative result is possible with early infection; if in doubt, repeat testing after 7-14 days is appropriate. Antibodies are not used to assess response to therapy, as they can persist for a long time. [41]

Step 4. Specialized tests as indicated. Polymerase chain reaction can be used for arthritis to analyze synovial fluid; lumbar puncture with cerebrospinal fluid analysis for meningitis and radiculoneuritis; electrocardiography and monitoring for suspected carditis. The choice of method depends on the clinic. [42]

Table 3. Lyme disease serology: when to test

Situation	Is testing necessary?	Justification
Typical erythema migrans	Not required	Clinical diagnosis, low sensitivity of early serology
Neurological manifestations	Required	Confirmation of antibodies, additional analysis of cerebrospinal fluid as indicated
Cardiac manifestations	Required	Confirmation of antibodies, parallel ECG and observation
Arthritis	Required	High seropositivity, possible polymerase chain reaction of synovium

Table 4. Two-step serology algorithms

Algorithm	The first stage	The second stage	Notes
Standard two-stage	Enzyme-linked immunosorbent assay	Immunoblot	Historical standard
Modified two-stage	Enzyme-linked immunosorbent assay	Enzyme immunoassay of a different design	Regulator approved, comparable or better sensitivity in early stages

Differential diagnosis

Skin. Erythema migrans is distinguished from cellulitis, dermatophytosis, and local bite reactions. Southern tick-borne encephalitis (STE) in the southern United States is clinically similar but is caused by different agents and does not require the same testing and treatment. [43]

Nervous system. Facial nerve lesions are differentiated from idiopathic Bell's palsy and viral neuritis based on epidemiology and serology. Aseptic meningitis must be distinguished from enteroviral and herpetic meningitis. [44]

Heart. Conduction disturbances in Lyme disease are differentiated from myocarditis of other etiologies, drug effects, and congenital disorders. The combination with erythema migrans, season, and endemicity support the diagnosis of Lyme disease. [45]

Systemic symptoms. Fever, myalgias, and cytopenias may be due to coinfections such as anaplasmosis and babesiosis, which requires targeted laboratory evaluation if initial therapy with doxycycline is ineffective.[46]

Table 5. Key differences between erythema migrans and its imitators

State	Centrifugal growth	Blurred appearance in the center	Pain and warmth	Reducing deadlines to a bite
Erythema migrans	Eat	Often	Usually no	Yes, 3-30 days
Cellulite	No	No	Expressed	Often without communication
Dermatophytosis	Slow	May be	No	No
Local reaction to the bite	No	No	Moderate	Immediately, it does not grow

Treatment

The early localized stage with erythema migrans in adults is treated with short courses orally. Doxycycline 100 mg twice daily is prescribed for 10 days; alternatives include amoxicillin 500 mg three times daily or cefuroxime axetil 500 mg twice daily for 14 days. The choice takes into account age, pregnancy, and contraindications. [47]

In the early disseminated stage without meningitis, the same regimens per os for 14 days are possible. In cases of cranial nerve damage without signs of meningitis in adults, per os doxycycline is justified with comparable efficacy according to European guidelines. [48]

Neuroborreliosis with meningitis or radiculoneuritis requires 14-21 days of antibacterial therapy: ceftriaxone 2 g intravenously once a day, or doxycycline orally 200 mg per day in 1-2 doses for uncomplicated cases. The choice of route depends on the severity, tolerability, and availability of observation. [49]

Lyme carditis is treated for 14-21 days: in case of mild blockade, therapy is administered orally; in case of severe blockade, therapy is started with intravenous ceftriaxone, followed by a transition to orally to complete the course; short-term temporary cardiac pacing is possible. [50]

Lyme arthritis is treated for 28 days orally with doxycycline, amoxicillin, or cefuroxime axetil. If the response is incomplete, a second course or alternatives are discussed based on recommendations, excluding unjustified long-term or combination regimens. [51]

Pregnancy. Amoxicillin or cefuroxime axetil are preferred for 14–21 days; tetracyclines, including doxycycline, are generally avoided. The decision to administer a single postexposure dose of doxycycline in high-risk individuals is discussed on an individual basis after assessing the benefits and risks. [52]

Children. Short courses of doxycycline in children, including young children, are acceptable according to current guidelines for certain indications; the dose is calculated as 4.4 mg/kg per day for neuroborreliosis or a single dose of 4.4 mg/kg for post-exposure prophylaxis in high-risk settings. [53]

Post-treatment symptoms. Repeated or prolonged courses of antibiotics do not improve outcomes in the absence of signs of active infection. Symptomatic therapy, rehabilitation, and observation are recommended. [54]

Table 6. Basic antibacterial therapy regimens in adults

Situation	Preparation	Dosage	Duration
Erythema migrans	Doxycycline	100 mg 2 times a day per os	10 days
Erythema migrans	Amoxicillin	500 mg 3 times a day per os	14 days
Erythema migrans	Cefuroxime axetil	500 mg 2 times a day per os	14 days
Neuroborreliosis	Ceftriaxone	2 g once a day intravenously	14-21 days
Carditis	Ceftriaxone → oral regimens	Around the clinic	14-21 days
Arthritis	Doxycycline or alternatives	By drug	28 days

Prevention

Primary prevention includes protective clothing, skin examinations immediately after outdoor activities, the use of repellents based on diethyltoluamide, picaridin, and IR3535, and the treatment of clothing with permethrin. Proper tick removal with fine tweezers reduces the risk of transmission. [55]

Post-exposure prophylaxis. In some cases, a single dose of doxycycline is indicated within 72 hours of tick removal: 200 mg for adults and 4.4 mg/kg for children, if high-risk criteria are met. If doxycycline is contraindicated, alternatives for prophylaxis are not recommended. [56]

A human vaccine has not yet been licensed, although late-stage clinical trials of a candidate vaccine are underway. Therefore, the emphasis is on individual protective measures and early recognition of symptoms. [57]

Prevention of coinfections is the same as prevention of Lyme disease, as the vectors are the same. If fever develops after a tick bite, early medical attention is important, even in the absence of a skin rash. [58]

Table 7. Decision on post-exposure prophylaxis with doxycycline

Criterion	Yes	No
Tick species - Ixodes
Region of high endemicity
The tick feeds for a long time, the tick is well-fed
Deleted ≤ 72 hours ago
There are no contraindications to doxycycline.

Forecast

With early initiation of therapy, the prognosis is favorable: most patients recover completely without lasting consequences. Reinfection is possible with a new tick bite; immunity is not persistent or protective in the long term. [59]

Neurological and cardiac complications are reversible within weeks and months with timely diagnosis. Timely treatment and monitoring reduce the risk of residual effects. [60]

With the articular form, relapses of inflammation are possible, requiring re-evaluation and sometimes additional therapy as recommended. Long-term courses without indications do not improve outcome and are not recommended. [61]

Post-treatment symptoms in some patients gradually resolve with supportive care and rehabilitation. The key to a favorable outcome is early diagnosis, appropriate treatment regimen selection, and control of risk factors for re-bite. [62]

FAQ

Is it possible to get Lyme disease again after having it?
Yes, reinfection is possible with a new bite from an infected tick; a previous infection does not provide reliable long-term immunity. [63]

Is it necessary to undergo testing for typical erythema migrans?
No, with a characteristic clinical picture, treatment is initiated without delay for laboratory confirmation, as early serology is often negative. [64]

Is the disease dangerous during pregnancy and how is it treated?
With timely treatment, the outcome is favorable; amoxicillin or cefuroxime axetil are preferred; tetracyclines are generally avoided. [65]

When is a single dose of doxycycline prophylaxis appropriate after a tick bite?
Within 72 hours if the risk is high: Ixodes species, endemic region, prolonged tick feeding, no contraindications. Dose: 200 mg for adults, 4.4 mg/kg for children. [66]

Are prolonged or repeated courses of antibiotics necessary for persistent complaints?
No, additional antibiotics are not recommended without signs of active infection; supportive and rehabilitative measures are used. [67]