Lyme Disease
Clinical Questions
- Who is at risk of acquiring Lyme disease?
- What are the clinical manifestations of Lyme disease?
- When is serologic testing for Lyme disease indicated?
- What is the recommended treatment for Lyme disease?
- What are the measures to prevent Lyme disease?
Epidemiology
Lyme disease is the leading vector-borne illness in the United States. Most cases occur in the Mid-Atlantic, Northeast, and North Central regions, and eight states (Connecticut, Rhode Island, New York, New Jersey, Delaware, Pennsylvania, Maryland, and Wisconsin) account for 91% of the cases reported to the Centers for Diseases Control and Prevention (CDC). Lyme disease is also common in parts of Europe and Asia with a temperate climate.
The spirochete Borrelia burgdorferi sensu lato is the agent of Lyme disease. At least three genospecies can cause human disease: B. burgdorferi sensu stricto, B. garinii, and B. afzelii. B. burgdorferi sensu stricto is the only genospecies associated with human disease in the United States, but all three genospecies occur in Europe and Asia. In the United States, the most common vectors of infection are from the Ixodes family (the deer tick). Ticks in the nymph stages are similar in size to a poppy seed, whereas adult ticks are the size of a sesame seed (Figure 7).
Figure 7. Ixodes scapularis, the Major North American Tick Vector for Lyme Borreliosis.
Clinical Features
For clinical purposes, Lyme disease is divided into early localized, early disseminated, and late stages (Table 13
). Lyme disease usually begins in the summer with the characteristic skin lesion, erythema migrans. This seasonal preference reflects the peak of both the activity of Ixodes nymphs and human outdoor activity. The incubation period from infection to onset of erythema migrans is typically 7 to 14 days. Because of the small size of the ticks, most patients do not remember the preceding tick bite. Classically, erythema migrans starts as a red papule at the site of the bite, which gradually expands to an annular lesion with red borders and partial central clearing. However, less than 35% of patients in the United States have lesions with central clearing. Less commonly, the center of the lesion may appear vesicular or necrotic (Figure 8). Constitutional symptoms, arthralgias and myalgias, and severe fatigue are common. Regional lymphadenopathy may also occur. Erythema migrans may be absent in approximately 10% of patients with early Lyme disease (Steere, Bartenhagen et al.; Nadelman et al.; Strle et al.).
Figure 8. Erythema Migrans Lesions.
After several days or weeks, the spirochete may spread hematogenously, and infected patients may develop multiple erythema migrans lesions (Figure 8), as well as neurologic, cardiac, and rheumatologic problems. Lymphocytic meningitis, motor or sensory radiculoneuritis, and cranial neuropathy (particularly facial palsy that may be bilateral), are the most common neurologic abnormalities and occur in 15% to 20% of patients. Cardiac involvement occurs in 4% to 8% of patients. The most common feature is a fluctuating atrioventricular block. Asymmetric oligoarticular arthritis, especially involving the knees, occurs in about 60% of patients at a mean of 6 months from the onset of the disease (Steere, Schoen et al.). These early signs can resolve even if the patient is untreated. Borrelial lymphocytoma is a firm, painless, bluish-red nodular lesion that is usually localized on the earlobe or nipple. It occurs almost exclusively in Europe and is associated with B. afzelli and B. garinii infection.
The late manifestations of Lyme disease occur more than 1 year after infection. Chronic arthritis typically involves one or two large joints, with preference for the knees, and occurs in about 11% of untreated patients with erythema migrans. If untreated, the arthritis may persist or may resolve spontaneously. A few patients have persistent arthritis after receiving antibiotic therapy; this is classified as treatment-resistant Lyme arthritis. An autoimmune reaction as a result of molecular mimicry between outer surface protein A (OspA) of B. burgdorferi and human leukocyte function-associated antigen 1 (hLFA-1) has been proposed as the mechanism of this persistent arthritis (Gross et al.). A subacute mild encephalopathy affecting memory and concentration is the most common form of chronic neuroborreliosis. It is usually associated with headache, mild depression, irritability, fatigue, and sleep disturbances. The symptoms are subtle, and the cerebrospinal fluid is often normal. Patients can also present with chronic mild axonal polyneuropathy manifested as distal paresthesias, and, less commonly, as radicular pain. Rarely, an encephalomyelitis or leukoencephalitis can occur (Logigian et al. — Successful treatment; Logigian et al. — Chronic neurological manifestations). Acrodermatitis chronica atrophicans is a chronic skin disease that occurs in Europe and Asia and is primarily associated with B. afzelii infection. The skin lesions are usually found on the extensor surfaces of the extremities. They begin insidiously as an inflammatory infiltrate that subsequently becomes indurated with reddish-violaceous discoloration and then progress to atrophy of the skin over a period of years. Patients may have an associated sensory neuropathy.
Lyme disease is a reportable disease. For surveillance purposes, it is defined as the presence of an erythema migrans rash > 5 cm in diameter or laboratory confirmation of infection with evidence of at least one manifestation of musculoskeletal, neurologic, or cardiovascular disease.
Post-Lyme disease syndrome, or chronic Lyme disease, is an ill-defined condition that occurs in some patients after treatment for Lyme disease. It is characterized by nonspecific symptoms of fatigue, sleep disorders, headache, memory and concentration difficulties, myalgias, and arthralgias that persist for longer than 6 months after completion of adequate antimicrobial therapy. The cause of this syndrome is currently unknown.
Laboratory Evaluation
The diagnosis of Lyme disease is based primarily on clinical findings. Serologic testing is the most commonly used corroborative laboratory test. The American College of Physicians has published a position paper about laboratory evaluation for the diagnosis of Lyme disease (Guidelines for laboratory evaluation). Physicians should try to determine the pretest probability of Lyme disease before ordering serologic studies and only employ serologic testing when the pretest probability is between 0.2 and 0.8. Serologic testing is not recommended for patients with erythema migrans. These patients should be treated based on the clinical diagnosis, as only 30% will have positive serologic test results. Serologic testing is most useful for diagnosing suspected extracutaneous Lyme disease. When serologic testing is indicated, the CDC recommendations are to use a two-step approach, with the initial test being a sensitive enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody test. If the results are positive or equivocal, supplemental testing by Western blot analysis is recommended. In persons who have been ill for longer than 1 month, a positive IgM test result alone is likely to be a false-positive result. Serologic diagnosis for Lyme disease has improved substantially in the United States. Unfortunately, there are still problems caused by poor standardization of the tests, poor interlaboratory and intralaboratory reproducibility of results, and high numbers of both false-positive and false-negative results, depending on the tested population. Serologic tests do not distinguish between active and inactive infection, and patients may continue to be seropositive for years, even after adequate antibiotic treatment. Neither positive serologic test results nor a history of previous Lyme disease ensures that a person has protective immunity.
Intrathecal Antibody Production
The concomitant analysis of serum and cerebrospinal fluid (CSF) to demonstrate local synthesis of anti-Borrelia antibodies (called the CSF index, which is considered positive when the antibody titer in CSF exceeds the titer in serum) is regarded by some as a requirement for the diagnosis of neurologic Lyme disease. This test is commonly positive in European patients. However, intrathecal antibody production seems to be much less common in the United States, and a negative test result does not exclude the diagnosis.
Culture
Culture of B. burgdorferi is seldom useful in clinical practice. It requires a special bacteriologic medium (modified Barbour-Stoenner-Kelly medium) and a prolonged period of observation (2 to 6 weeks), owing to the slow multiplication of the bacteria. B. burgdorferi can be cultured from 40% to 80% of biopsy specimens taken from erythema migrans lesions and from about 25% of blood samples from patients with early disseminated disease. However, B. burgdorferi is very rarely isolated from patients with later disease, and the diagnostic usefulness of this procedure is limited.
Polymerase Chain Reaction
Polymerase chain reaction (PCR) has been used to amplify genomic DNA of B. burgdorferi in skin, blood, cerebrospinal fluid, and synovial fluid. It seems to be most useful in patients with Lyme arthritis. B. burgdorferi DNA has been detected in synovial fluid samples from 85% of the patients with Lyme arthritis (Nocton et al.). However, the sensitivity of PCR determinations in cerebrospinal fluid from patients with neuroborreliosis has been much lower (less than 40% in patients with acute neuroborreliosis). Nested PCR may increase the sensitivity of the assay, but because of the high risk of contamination, it cannot be used routinely as a diagnostic tool until this problem is overcome.
Treatment
Lyme disease is usually treated successfully with standard antibiotic regimens (Tables 14 and 15). Early and uncomplicated infection, including infection associated with isolated cranial nerve palsy, usually responds satisfactorily to treatment with oral antibiotics. Doxycycline, 100 mg twice a day for adults, is the drug of choice, but it is contraindicated for children less than 9 years old and for pregnant or lactating women. An advantage of doxycycline is that it is also effective against the agent of human granulocytic ehrlichiosis. Patients should be advised to wear sunscreen and avoid sun exposure, as doxycycline can cause photosensitivity. Amoxicillin, 500 mg three times a day, and cefuroxime axetil, 500 mg twice a day, are second-line alternatives. Oral macrolides are considered a third-line alternative, as their clinical efficacy has been less than that of the ß-lactams and tetracyclines. The recommended duration of therapy varies from 14 to 28 days. Parenteral antibiotics are generally recommended for treating neurologic Lyme disease and more severe cardiac disease (first-degree atrioventricular block a with a PR interval of greater than 0.3 second and any higher-degree atrioventricular block). Intravenous ceftriaxone, 2 g/d for 4 weeks, is the most commonly used parenteral therapy, but intravenous cefotaxime, 2 g three times a day, and intravenous penicillin G, 20 million units/d in divided doses, can also be used. Patients with Lyme encephalopathy have gradual improvement of their symptoms, usually starting a few months after completion of therapy, and continue to slowly improve for up to 1 to 2 years. For patients with Lyme arthritis (without neurologic involvement), oral anti-biotics are usually given for 30 to 60 days. Patients who do not respond should receive intravenous therapy for 30 days. For patients with treatment-resistant Lyme arthritis, administration of anti-inflammatory agents is recommended.
Co-Infection
Ixodes ticks are also vectors for human granulocytic ehrlichiosis and babesiosis. In Europe and Asia, these ticks also transmit tick-borne encephalitis. Concurrent infection should be considered in a patient with unusually severe features of Lyme disease or with atypical features.
Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW, et al. The early clinical manifestations of Lyme disease. Ann Intern Med. 1983;99: 76-82. PubMed Link
Nadelman RB, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Cooper D, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med. 1996; 100:502-8. PubMed Link
Strle F, Nadelman RB, Cimperman J, Nowakowski J, Picken RN, Schwartz I, et al. Comparison of culture-confirmed erythema migrans caused by Borrelia burgdorferi sensu stricto in New York State and by Borrelia afzelii in Slovenia. Ann Intern Med. 1999;130:32-6. PubMed Link Annals Link
Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107:725-31. PubMed Link
Gross DM, Forsthuber T, Tary-Lehmann M, Etling C, Ito K, Nagy ZA, et al. Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science. 1998;281:703-6. PubMed Link
Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis. 1999;180:377-83. PubMed Link
Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323:1438-44. PubMed Link
Guidelines for laboratory evaluation in the diagnosis of Lyme disease. American College of Physicians. Ann Intern Med. 1997;127:1106-8. PubMed Link Annals Link
Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med. 1994;330:229-34. PubMed Link
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Page posted: 2/10/04
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