Lyme disease

Tatyana Zaikina — Fri, 22 Dec 2023 13:20:42 +0000

Tatyana Zaikina

Lyme disease is an infectious disease caused by the spirochete Borrelia burgdorferi, which is transmissible during a tick bite.

Prevalence

Lyme disease is the most common transmissible disease in the northern hemisphere, affecting thousands of people each year. For example, about 40 cases of Lyme disease per 100 thousand population are registered in the USA every year. Outbreaks of infection are usually registered in the spring-autumn period.

Etiology

The causative agent of Lyme disease is the spirochete Borrelia burgdorferi, which enters the human body when bitten by an ixodid tick.

Pathogenesis

When a spirochete enters the body, the following occurs:

the immune system of an infected person destroys the spirochete or
The spirochete remains viable and causes erythema migrans, a skin lesion characteristic of Lyme disease or
the spirochete spreads for several weeks through the lymphatics or blood.

After entering the bloodstream, the spirochete shows a distinct tropism to the skin, heart, central nervous system (CNS), joints, and eyes.

Clinical picture

The interval between a tick bite and the appearance of the first symptoms of the disease is usually from 7 to 14 days, but in some cases it can increase to several months.

In the course of Lyme disease, early and late periods are conventionally distinguished. The early period consists of an early localized stage and an early disseminated stage.

The early localized stage is characterized by fever and migrating erythema at the site of the tick bite. Gradually increasing in diameter over several days (usually more than 5 cm in diameter), the center of the spot becomes lighter, resembling a “target” or “bull’s eye”. Erythema migrans is accompanied by an increase in local temperature, but rarely itches or hurts. Erythema migrans persists for several days or weeks, then disappears, leaving behind pigmentation or scaling.

In one-third of patients, the disease ends on its own at this stage, and in two-thirds, it turns into a disseminated one, which is characterized by the appearance of signs of damage to the nervous system, heart, joints, and eyes.

The early disseminated stage develops 3-12 weeks after the primary infection and is characterized by the appearance of general weakness, fever, muscle pain, neurological symptoms, joint, eye, and cardiac symptoms.

When the central nervous system is affected, patients complain of a severe headache, neck stiffness; facial asymmetry occurs when the facial nerve is damaged; when peripheral nerves are affected, there is a shooting pain, numbness and tingling in the hands and feet.

Lyme arthritis is accompanied by the appearance of severe pain and swelling of mainly large joints, periodic muscle and tendon pain.

Heart damage in Lyme disease is characterized by the development of myocarditis or myopericarditis. Patients complain of chest pain, shortness of breath, heart rhythm and/or conduction disturbances. Often patients with Lyme carditis have a violation of AV conduction. The degree of AV block can rapidly progress from first-degree AV block to complete AV block.

A rare skin manifestation of early Lyme borreliosis is the so-called borreliosis lymphocytoma – a single bluish-red nodular formation that can be localized on the earlobe, near the nipple or in the scrotum.

Late-stage Lyme disease occurs months or years after the onset of the disease. At the late stage of the disease, patients develop aseptic meningitis, Bell’s palsy, impaired cognitive functions, and arthritis. In addition, chronic atrophic acrodermatitis often occurs – a slowly progressive skin lesion with the appearance of blue-red spots mainly on the extensor surfaces of the distal parts of the limbs and subsequent skin atrophy.

Classification

Depending on the period of the disease, the following are distinguished: early (localized and disseminated stages) and late period.

The early period of Lyme Borreliosis is characterized by the development of migratory erythema at the site of tick suction and spread of infection, which is manifested by the development of benign lymphocytoma of the skin, damage to the nervous system (neuritis of the facial nerve, polyradiculopathy, acute meningoencephalitis), heart (myocarditis with AV conduction disorders), and joints.

The late period of Lymboreliosis is characterized by various organ lesions of autoimmune genesis, in particular, recurrent arthritis of mainly large joints, chronic encephalomyelitis, dilated cardiomyopathy, chronic atrophic acrodermatitis.

Depending on the stage of the disease, the following are distinguished: early localized, early disseminated, late stage.

Depending on the variant of the course, they are distinguished: acute (lasts up to 3 months), subacute (lasts from 3 to 6 months), chronic course (lasts more than 6 months).

Depending on the predominant clinical symptoms, the following are distinguished: skin, joint, cardiac, neurological, mixed forms.

Depending on the severity, the following are distinguished: mild, moderate, and severe.

A mild course of lymoborreliosis is characterized by a moderately pronounced intoxication syndrome, an increase in body temperature up to 38 0 ^C , the presence of migratory erythema in the absence of damage to the nervous system, heart or joints.

A moderately severe course of lymoborreliosis is characterized by a pronounced intoxication syndrome, an increase in body temperature to 38-39 ⁰ C, the presence of migratory erythema, minor damage to the nervous system, heart or joints.

A severe course of lymoborreliosis is characterized by a pronounced intoxication syndrome, an increase in body temperature above 39 ⁰ C, moderate or severe damage to the nervous system (meningitis) or heart (AV-blockade II-III stage, pronounced myocarditis).

Diagnostics

The diagnosis of Lyme borreliosis is established on the basis of a characteristic clinical picture, anamnestic data and serological confirmation.

When analyzing the results of a serological test, it is important to take into account the dynamics of the serological response to infection.

During the first 2-4 weeks from the moment of the tick bite in patients with erythema migrans, the result of the serological test may be false-negative. In this case, in the case of a high probability of Lyme disease, it is recommended to repeat the serological examination after 4-6 weeks.

A positive result of a test for the presence of antibodies can indicate both an active infectious process and a transferred infection, because both classes of immunoglobulins can persist in the blood serum for months and even years.

In some cases, a Borrelia antibody test result may be false-positive due to the presence of cross-reactive antibodies to other microbes or an autoimmune disease. That is why it is appropriate to conduct a serological examination only in case of high probability of Lyme disease.

In view of the above, the following two-level procedure is recommended for serological confirmation of the diagnosis:

• Stage 1: Enzyme immunoassay (IFA) or immunofluorescence assay (IFA) to determine the titer of IgG and/or IgM

• Stage 2: Western blotting, which is carried out in case of a positive or doubtful result of a blood test for antibody titer

To identify the DNA of the causative agent, polymerase chain reaction (PCR) is performed, however, according to existing recommendations, it is of secondary importance in the diagnosis of Lyme borreliosis.

In addition to laboratory confirmation of Lyme disease, patients undergo additional examination methods depending on clinical symptoms.

In case of heart damage, it is advisable to conduct electrocardiography, transthoracic echocardiography, blood test for troponin-I and others. In patients with Lyme carditis, signs of myopericarditis, heart rhythm and/or conduction disturbances are found.

When joints are affected, in some cases, it is advisable to perform an arthrocentesis followed by an examination of the synovial fluid. In patients with Lyme arthritis, the synovial fluid is usually inflammatory, with cell counts ranging from 500 to 98,000/μl. In adult patients, the fluid should also be checked for crystals to rule out gout and pseudogout. Detection of B. burgdorferi DNA in synovial fluid is not a reliable test for active joint infection in Lyme disease.

In the case of damage to the central nervous system, in particular, when meningitis is suspected, a lumbar puncture is performed followed by analysis of the cerebrospinal fluid. In patients with meningitis caused by Lyme disease, analysis of the cerebrospinal fluid (CSF) often shows moderate pleocytosis (< 1000 cells/μl) with a predominance of lymphocytes. Patients with meningitis usually have an elevated protein concentration (>50 mg/dL) but a normal glucose level (45-80 mg/dL). Oligoclonal bands specific for B burgdorferi may be present.

Differential diagnosis

Depending on the clinical manifestations, Lyme disease is differentiated into the following conditions:

• Ankylosing spondylitis and rheumatoid arthritis

• Contact dermatitis

• Gout and pseudogout

• Annular granuloma

• Prion diseases

• Bell’s palsy

• Chronic fatigue syndrome (myalgic encephalomyelitis)

• Fibromyalgia

• Juvenile rheumatoid arthritis

• Systemic lupus erythematosus (SLE)

• Other diseases transmitted by ticks

Specialist consultations

In some cases, in particular when it is necessary to exclude other causes of existing complaints, there is a need to consult related specialists, such as a rheumatologist, dermatologist, cardiologist, neurologist, psychotherapist.

Treatment

The main goals of treatment are to eliminate the symptoms and signs of infection, prevent the development of complications and relapses of active infection.

For this, patients with confirmed Lyme disease are prescribed antibiotic therapy. The drugs of choice are doxycycline, amoxicillin, cefuroxime axetil. In case of intolerance to doxycycline and beta-lactams, azithromycin is used.

Drug therapy of erythema migrans

The duration of antibiotic therapy for patients with erythema migrans depends on the selected drug: doxycycline is prescribed at a dose of 100 mg 2 times a day for 10 days, amoxicillin is prescribed at a dose of 500 mg 3 times a day for 14 days or cefuroxime axetil at a dose of 500 mg 2 times for day for 14 days. In case of intolerance to doxycycline or beta-lactams, azithromycin is used for 5-10 days.

Antibiotic therapy of other clinical manifestations of Lyme disease has certain features.

Drug therapy of acute neurological manifestations

In patients with meningitis associated with Lyme disease, cranial neuropathy, radiculoneuropathy, or other manifestations of peripheral nervous system involvement, intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline should be used instead of other antimicrobial agents. The recommended duration of antibiotic therapy is 14–21 days.

Drug therapy of carditis

Outpatient treatment is indicated for patients: without clinical manifestations of myopericarditis, without arrhythmia, without II or III degree AV blockade, without I degree blockade with a PR interval ≥0.3 seconds. Outpatients with heart damage are prescribed oral antibacterial drugs: doxycycline, amoxicillin, cefuroxime, azithromycin.

Inpatient treatment is indicated for patients: with clinical manifestations of myopericarditis, with arrhythmias, with II or III degree AV block, with I degree AV block with a PR interval ≥0.3 sec. Inpatient patients with heart damage are prescribed parenteral antibacterial drugs: ceftriaxone in IV, cefotaxime IV, benzylpenicillin IV or IV. After the appearance of positive dynamics, it is possible to switch to oral antibiotics.

The duration of antibiotic therapy for Lyme carditis should be 14-21 days.

For patients with symptomatic bradycardia due to heart damage in Lyme disease that is not amenable to medical treatment, temporary electrical cardiostimulation is recommended.

Drug therapy of arthritis

Patients with Lyme arthritis are prescribed doxycycline, amoxicillin, or cefuroxime. The duration of antibiotic therapy for joint damage should be 28 days.

Borreliosis lymphocytoma

Antibiotic therapy with doxycycline, amoxicillin or cefuroxime for 14 days is recommended for patients with borreliosis lymphocytoma.

Chronic atrophic acrodermatitis

Antibiotic therapy with doxycycline, amoxicillin or cefuroxime for 21-28 days is recommended for patients with chronic atrophic acrodermatitis.

Clinical picture	Treatment of choice	Alternative treatment
Erythema migrans	Doxycycline 100 mg 2 times a day orally (PO) for 10 days or Amoxicillin 500 mg 3 times a day PO for 14 days or Cefuroxime 500 mg 2 times a day PO for 14 days	Azithromycin 500 mg once a day p/o for 5-10 days
Damage to the nervous system	Ceftriaxone 2 g once a day IV for 14-21 days or Cefotaxime 2 g 3 times a day IV for 14-21 days or Benzylpenicillin sodium salt 2.4 g every 4-6 hours IV or IV for 14-21 days
Heart damage (without clinical manifestations of myopericarditis, without arrhythmia, without AV block II or III degree, without block I degree with PR interval ≥0.3 sec.)	Doxycycline 100 mg 2 times a day orally (p/o) for 14-21 days or Amoxicillin 500 mg 3 times a day p/o for 14-21 days or Cefuroxime 500 mg 2 times a day p/o for 14-21 days	Azithromycin 500 mg once a day p/o
Heart damage (with clinical manifestations of myopericarditis, with arrhythmias, with II or III degree AV block, with I degree AV block with a PR interval ≥0.3 sec.)	Ceftriaxone 2 g once a day IV for 14-21 days or Cefotaxime 2 g 3 times a day IV for 14-21 days or Benzylpenicillin sodium salt 2.4 g every 4-6 hours IV or IV for 14-21 days
Damage to the joints	Doxycycline 100 mg 2 times a day orally (PO) for 28 days or Amoxicillin 500 mg 3 times a day PO for 28 days or Cefuroxime 500 mg 2 times a day PO for 28 days
Borreliosis lymphocytoma	Doxycycline 100 mg 2 times a day orally (PO) for 14 days or Amoxicillin 500 mg 3 times a day PO for 14 days or Cefuroxime 500 mg 2 times a day PO for 14 days
Chronic atrophic acrodermatitis	Doxycycline 100 mg 2 times a day orally (p/o) for 21-28 days or Amoxicillin 500 mg 3 times a day p/o for 21-28 days or Cefuroxime 500 mg 2 times a day p/o for 21-28 days

Tactics in case of ineffectiveness of antibiotic therapy

Patients who have persistent or recurrent nonspecific symptoms such as fatigue, pain, or cognitive impairment after recommended Lyme disease treatment, but who do not have objective evidence of reinfection or treatment failure, should not be given additional courses of antibiotic therapy.

Evidence of persistent infection or ineffectiveness of treatment is the preservation of objective signs of disease activity, such as arthritis, meningitis, or neuropathy.

Prevention

Individual protection measures

Persons at risk of infection should take personal protective measures to reduce the risk of being bitten by ticks and contracting the pathogens they transmit. To do this, when going to an area with a high probability of contact with ticks, it is recommended to wear light-colored clothes with long sleeves and pants, tuck your pants into socks or high shoes, and conduct a thorough check of your clothes and body after returning.

Use of repellents to prevent tick bites

For the prevention of tick bites, it is recommended to use products containing N,N-diethyl-meta-toluamide (DEET), picaridin, ethyl 3-(Nn-butyl-N-acetyl) aminopropionate (IR3535), oil of lemon eucalyptus (OLE), p-methane-3,8-diol (PMD), 2-undecanone or permethrin.

Removal of attached ticks

Given that the length of time a tick is attached to the skin is an extremely important predictor of developing Lyme disease (the likelihood of Lyme disease increases significantly after 36-48 hours), immediate removal of the attached tick is recommended. This is best done with clean, fine-tipped tweezers (or similar device) inserted between the body of the tick and the skin.

It is not advisable to burn the attached tick (with a match or other thermal intervention) or to use harmful chemicals or petroleum products to detach it.

After removing the tick, it is recommended to carry out a study to identify its species. But at the same time, it is not advisable to test the removed tick for B. Burgdorferi, because the presence or absence of this microorganism is not a reliable sign of the presence of infection.

Antibiotic prophylaxis

It is recommended to prescribe prophylactic antibiotic therapy for adults and children within 72 hours after removal of a high-risk tick.

The patient is prescribed a single dose of doxycycline at a dose of 200 mg for adults or 4.4 mg/kg (up to 200 mg) for children.

A tick bite is considered high-risk if it meets the following three criteria: the removed tick belongs to the Ixodes species; the bite occurred in a highly endemic area; the tick was attached for ≥36 hours.

If the tick bite is not high-risk, observation is recommended.

Post-Treatment Lyme Disease Syndrome ( PTLDS )

Post-treatment Lyme disease syndrome (PTLDS) is characterized by the presence of persistent (more than 6 months) symptoms (pain, fatigue, difficulty thinking) after the end of Lyme disease treatment.

The cause of this syndrome is unknown. Some experts believe that Borrelia burgdorferi can trigger an “autoimmune” reaction, causing symptoms that persist even after the infection has cleared. Other experts suggest that PTLDS is the result of a persistent but difficult-to-detect infection. Finally, some believe that the symptoms of PTLDS are due to other causes unrelated to Borrelia burgdorferi infection.

Unfortunately, there is no specific treatment for PTLDS. Studies have shown that long-term outcomes are no better for patients who receive additional long-term antibiotic treatment than for patients who receive placebo. Prolonged antibiotic treatment of Lyme disease is associated with serious, sometimes fatal, complications.

Patients with PTLDS usually improve over time, but this may take many months.

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Resources:

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clinical Infectious Diseases, Volume 72, Issue 1, 1 January 2021, Pages e1-e48. https://doi.org/10.1093/cid/ciaa1215
Official site of the Centers for Disease Control and Prevention. https://www.cdc.gov/lyme/treatment/index.html

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