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Lyme Disease

By Larry M. Bush, MD, Affiliate Professor of Clinical Biomedical Sciences; Affiliate Associate Professor of Medicine, Charles E. Schmidt College of Medicine, Florida Atlantic University; University of Miami-Miller School of Medicine
Maria T. Perez, MD, Associate Pathologist, Department of Pathology and Laboratory Medicine, Wellington Regional Medical Center, West Palm Beach

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Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia burgdorferi. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by neurologic, cardiac, or joint abnormalities. Diagnosis is primarily clinical in early-stage disease, but serologic testing can help diagnose cardiac, neurologic, and rheumatologic complications that occur later in the disease. Treatment is with antibiotics such as doxycycline or ceftriaxone.

The family Spirochaetales is distinguished by the helical shape of the bacteria. They are too thin to be visualized using routine microscopy but can be viewed using darkfield microscopy. There are 3 genera: Treponema, Leptospira, and Borrelia.


Lyme disease was recognized in 1976 because of close clustering of cases in Lyme, Connecticut and is now the most commonly reported tick-borne illness in the US. It has been reported in 49 states, but > 90% of cases occur from Maine to Virginia and in Wisconsin, Minnesota, and Michigan. On the West Coast, most cases occur in northern California and Oregon. Lyme disease also occurs in Europe, across the former Soviet Union, and in China and Japan. Onset is usually in the summer and early fall. Most patients are children and young adults living in heavily wooded areas.

Lyme disease is transmitted primarily by 4 Ixodes sp worldwide:

  • Ixodes scapularis (the deer tick) in the northeastern and north central US

  • I. pacificus in the western US

  • I. ricinus in Europe

  • I. persulcatus in Asia

In the US, the white-footed mouse is the primary animal reservoir for Borrelia burgdorferi and the preferred host for nymphal and larval forms of the deer tick. Deer are hosts for adult ticks but do not carry Borrelia. Other mammals (eg, dogs) can be incidental hosts and can develop Lyme disease. In Europe, sheep are hosts for the adult tick.

Deer tick.


B. burgdorferi enters the skin at the site of the tick bite. After 3 to 32 days, the organisms migrate locally in the skin around the bite, spread via the lymphatics to cause regional adenopathy or disseminate in blood to organs or other skin sites. Initially, an inflammatory reaction (erythema migrans) occurs before significant antibody response to infection (serologic conversion).

Symptoms and Signs

Lyme disease has 3 stages:

  • Early localized

  • Early disseminated

  • Late

The early and late stages are usually separated by an asymptomatic interval.

Early localized

Erythema migrans (EM), the hallmark and best clinical indicator of Lyme disease, is the first sign of the disease. It occurs in at least 75% of patients, beginning as a red macule or papule at the site of the tick bite, usually on the proximal portion of an extremity or the trunk (especially the thigh, buttock, or axilla), between 3 and 32 days after a tick bite. Because tick nymphs are so small, most patients do not realize that they have been bitten.

The area expands, often with clearing between the center and periphery resembling a bull’s eye, to a diameter 50 cm. Darkening erythema may develop in the center, which may be hot to the touch and indurated. Without therapy, EM typically fades within 3 to 4 wk.

Evanescent lesions may appear as EM resolves. Mucosal lesions do not occur. Apparent recurrences of EM lesions after treatment are caused by reinfection, rather than relapse, because the genotype identified in the new lesion differs from that of the original infecting organism.

Early disseminated

Symptoms of early-disseminated disease begin days or weeks after the appearance of the primary lesion, when the bacteria spread through the body. Soon after onset, nearly half of untreated patients develop multiple, usually smaller annular secondary skin lesions without indurated centers. Cultures of biopsy samples of these secondary lesions have been positive, indicating dissemination of infection.

Patients also develop a musculoskeletal, flu-like syndrome, consisting of malaise, fatigue, chills, fever, headache, stiff neck, myalgias, and arthralgias that may last for weeks. Because symptoms are often nonspecific, the diagnosis is frequently missed if EM is absent; a high index of suspicion is required. Frank arthritis is rare at this stage. Less common are backache, nausea and vomiting, sore throat, lymphadenopathy, and splenomegaly.

Symptoms are characteristically intermittent and changing, but malaise and fatigue may linger for weeks. Some patients develop symptoms of fibromyalgia. Resolved skin lesions may reappear faintly, sometimes before recurrent attacks of arthritis, in late-stage disease.

Neurologic abnormalities develop in about 15% of patients within weeks to months of EM (generally before arthritis occurs), commonly last for months, and usually resolve completely. Most common are lymphocytic meningitis (CSF pleocytosis of about 100 cells/μL) or meningoencephalitis, cranial neuritis (especially Bell palsy, which may be bilateral), and sensory or motor radiculoneuropathies, alone or in combination.

Myocardial abnormalities occur in about 8% of patients within weeks of EM. They include fluctuating degrees of atrioventricular block (1st-degree, Wenckebach, or 3rd-degree) and, rarely, myopericarditis with chest pain, reduced ejection fractions, and cardiomegaly.


In untreated Lyme disease, the late stage begins months to years after initial infection. Arthritis develops in about 60% of patients within several months, occasionally up to 2 yr, of disease onset (as defined by EM). Intermittent swelling and pain in a few large joints, especially the knees, typically recur for several years. Affected knees commonly are much more swollen than painful; they are often hot, but rarely red. Baker cysts may form and rupture. Malaise, fatigue, and low-grade fever may precede or accompany arthritis attacks. In about 10% of patients, knee involvement is chronic (unremittent for 6 mo).

Other late findings (occurring years after onset) include an antibiotic-sensitive skin lesion (acrodermatitis chronica atrophicans) and chronic CNS abnormalities, either polyneuropathy or a subtle encephalopathy with mood, memory, and sleep disorders.


  • Clinical evaluation, supported by acute and convalescent serologic testing

EM is usually diagnosed clinically because it develops before serologic tests become positive (1).

Cultures of blood and relevant body fluids (eg, CSF, joint fluid) may be obtained, primarily to diagnose other pathogens.

Acute (IgM) and convalescent (IgG) antibody titers 2 wk apart may be helpful; positive enzyme-linked immunosorbent assay (C6 ELISA) titers should be confirmed by Western blot. However, seroconversion may be late (eg, > 4 wk) or occasionally absent (eg, if patients received prior antibiotic therapy), and positive IgG titers alone represent previous exposure. If only IgM bands are detected on Western blot, especially long after exposure, the results are often false positive. PCR testing of CSF or synovial fluid is often positive when those sites are involved.

Consequently, diagnosis of Lyme disease depends on both test results and the presence of typical findings. A classic EM rash strongly suggests Lyme disease, particularly when supported by other elements (eg, recent tick bite, exposure to endemic area, typical systemic symptoms).

In areas where Lyme disease is endemic, many patients report arthralgias, fatigue, difficulty concentrating, or other nonspecific symptoms. Few patients who have these symptoms but have had no history of EM or other symptoms of early-localized or early-disseminated Lyme disease actually have Lyme disease. In such patients, elevated IgG titers (with normal IgM titers) indicate past exposure, not current or persistent infection, and may, if misinterpreted, lead to long and unnecessary courses of antibiotic therapy. There is no evidence linking B. burgdorferi infection to this fibromyalgia-like or chronic fatigue–like syndrome, often termed chronic Lyme disease.

Differential diagnosis

In the absence of rash, diagnosis is more difficult.

Early-disseminated disease may mimic juvenile idiopathic arthritis in children and reactive arthritis and atypical rheumatoid arthritis in adults. Findings that are often present in rheumatoid arthritis but not Lyme disease include morning stiffness, subcutaneous nodules, iridocyclitis, mucosal lesions, rheumatoid factor, and antinuclear antibodies. Late-stage Lyme disease lacks axial involvement, which distinguishes it from spondyloarthropathies with peripheral joint involvement.

In the US, human granulocytic anaplasmosis (a rickettsial infection) and babesiosis are also transmitted by I. scapularis and have a common geographic distribution in the northeastern and upper Midwest. Patients ill with any one of the diseases transmitted by I. scapularis may be concurrently infected with the other diseases it transmits; however, clinical coinfection with anaplasmosis is rare. A clinician should suspect that patients with Lyme disease also have

  • Babesiosis if they have hemolytic anemia and thrombocytopenia

  • Human granulocytic anaplasmosis if they have elevated aminotransferase levels, leukopenia, inclusion bodies in neutrophils, and/or thrombocytopenia

Acute rheumatic fever is considered in the occasional patient with migratory polyarthralgias and either an increased PR interval or chorea (as a manifestation of meningoencephalitis). However, patients with Lyme disease rarely have heart murmurs or evidence of a preceding streptococcal infection.

Human monocytotropic ehrlichiosis, which is caused by Ehrlichia chaffeensis and transmitted by the Lone Star tick, Amblyomma americanum, occurs mainly in the southeastern and south central US and is unlikely to be confused with Lyme disease.

In southern and mid-Atlantic states, bites from the A. americanum tick may result in an EM-like rash accompanied by nonspecific self-limited systemic symptoms and signs. No specific infectious agent has yet been identified as the cause of this disorder (called southern tick-associated rash illness).

Lyme disease may cause Bell palsy and, in summer, can manifest with a musculoskeletal aseptic meningitis syndrome that mimics other causes of lymphocytic meningitis or that mimics peripheral neuropathies.

Diagnosis reference

  • 1. Sanchez E, Vannier E, Wormser GP, et al: Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: A review. JAMA 315 (16):1767–1777, 2016. doi:10:1001/jama.2016.2284.


  • Multiple alternatives that vary with stage of disease but typically include amoxicillin, doxycycline, and ceftriaxone

Most features of Lyme disease respond to antibiotics, but treatment of early disease is most successful. In late-stage disease, antibiotics eradicate the bacteria, relieving the arthritis in most people. However, a few genetically predisposed people have persistent arthritis even after the infection has been eliminated because of continued inflammation. Guidelines for Antibiotic Treatment of Lyme Disease in Adults* shows adult treatment regimens for various presentations of Lyme disease. Treatment in children is similar except that doxycycline is avoided in children < 8 yr and doses are adjusted based on weight (see Table: Usual Doses of Commonly Prescribed Antibiotics).

For symptomatic relief, NSAIDs may be used. Complete heart block may require a temporary pacemaker. Tense knee joints due to effusions require aspiration. Some genetically predisposed patients with arthritis of the knee that persists despite antibiotic therapy may respond to arthroscopic synovectomy.

Guidelines for Antibiotic Treatment of Lyme Disease in Adults*



Early Lyme disease


500 mg po tid for 14–21 days


100 mg po bid for 14–21 days

Cefuroxime axetil

500 mg po bid for 14–21 days

Neurologic manifestations

Bell palsy (no other neurologic abnormalities):


As for early disease

Meningitis (with or without radiculoneuropathy or encephalitis):


2 g IV once/day for 14–28 days


2 g IV q 8 h for 14–28 days

Penicillin G

3–4 million units IV q 4 h for 14–28 days


100–200 mg po bid for 14–28 days

Cardiac manifestations


2 g IV once/day for 14–21 days

Penicillin G

3–4 million units IV q 4 h for 14–21 days


100 mg po bid for 14–21 days§


500 mg po tid for 14–21 days§

Arthritis (no neurologic involvement)


500 mg po tid for 28 days


100 mg po bid for 28 days

Cefuroxime axetil

500 mg po bid for 28 days


2 g IV once/day for 28 days

Penicillin G

3–4 million units IV q 4 h for 28 days

Acrodermatitis chronica atrophicans


500 mg po tid for 21 days


100 mg po bid for 21 days

*Pregnant women may receive amoxicillin 500 mg tid for 21 days. No treatment is necessary for pregnant women who are seropositive but asymptomatic.

Without neurologic, cardiac, or joint involvement. For early Lyme disease limited to a single erythema migrans lesion, 10 days is sufficient.

Optimal duration of therapy has not been established. There are no controlled trials of therapy > 4 wk for any neurologic manifestation of Lyme disease.

§For mild carditis with 1st-degree heart block, PR interval 30 sec, and normal ventricular function.

Treatment begins with an oral regimen, which is repeated if response is inadequate. If there was no response or symptoms worsen, parenteral ceftriaxone is given.

Adapted from Wormser GP, Dattwyler RJ, Shapiro ED, et al: The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:1089–1134, 2006.


Precautions against tick bite (see Tick Bite Prevention) should be taken by people in endemic areas. Deer tick nymphs, which attack humans, are small and difficult to see. Once attached to the skin, they gorge on blood for days. Transmission of B. burgdorferi does not usually occur until the infected tick has been in place for > 36 h. Thus, searching for ticks after potential exposure and removing them promptly can help prevent infection.

Routine use of antibiotic prophylaxis to prevent Lyme disease after a recognized tick bite is not recommended. Patients with a known tick bite can easily be instructed to monitor the bite site and seek care if rash or other symptoms occur; the diagnostic dilemma of Lyme is most prominent when there is no history of tick bite. A single dose of doxycycline 200 mg po has been shown to reduce the likelihood of Lyme disease after a deer tick bite. According to the 2006 Infectious Diseases Society of America (IDSA) guidelines, antibiotic prophylaxis should be offered only when all the following circumstances exist (1):

  • The attached tick can be reliably identified as an adult or nymphal I. scapularis tick.

  • The tick is estimated to have been attached ≥ 36 h (based on degree of engorgement of the tick with blood or time of exposure).

  • Prophylaxis can be started within 72 h of tick removal.

  • Patients live in or have visited an area where ≥ 20% of these ticks are infected with B. burgdorferi (generally only in parts of New England, parts of the mid-Atlantic states, and parts of Minnesota and Wisconsin).

  • Doxycycline is not contraindicated; it is contraindicated in pregnant or lactating women, children < 8 yr, and people who have had an allergic reaction to a tetracycline antibiotic.

Prevention reference

  • 1. Wormser GP, Dattwyler RJ, Shapiro ED, et al: The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43 (9):1089–1134, 2006.

Key Points

  • In the US, > 90% of Lyme disease cases occur from Maine to Virginia and in Wisconsin, Minnesota, and Michigan; Ixodes scapularis (the deer tick) is the primary vector in these areas.

  • In the US, the white-footed mouse is the primary animal reservoir for Borrelia burgdorferi and the preferred host for nymphal and larval forms of the deer tick; deer are hosts for adult ticks but do not carry Borrelia.

  • Lyme disease has 3 stages: early localized, early disseminated, and late.

  • Erythema migrans is the first and best clinical indicator; it occurs in ≥ 75% of patients.

  • In endemic areas, few patients who have arthralgias, fatigue, difficulty concentrating, or other nonspecific symptoms but who have had no history of EM or other symptoms of early-localized or early-disseminated Lyme disease actually have Lyme disease.

  • Diagnose clinically if typical rash is present; otherwise, do acute and convalescent serologic testing (ELISA confirmed by Western blot).

  • Treat with oral or parenteral antibiotics depending on disease manifestations.

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