Lyme borreliosis

Published on 19/03/2015 by admin

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Lyme borreliosis

David Banach and Gopi Patel

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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(Courtesy of Daniel Caplivski MD. Mount Sinai School of Medicine, New York, NY.)

Lyme disease is a multisystem illness caused by spirochetes of the genus Borrelia. In North America, the causative agent is Borrelia burgdorferi. In Europe, borreliosis is caused primarily by B. afzelii followed by B. garni although other Borrelia species have been implicated. Clinical manifestations of Lyme disease depend on the stage of illness and may be limited to the skin or involve the nervous system, joints, or heart. Currently, Lyme disease is the most common vector-borne disease in the US. It is endemic in the northeast, the mid-Atlantic, and parts of Wisconsin and Minnesota. The most common vector for Lyme disease in the US is the Ixodes scapularis tick. I. pacificus has been linked to transmission of B. burgdorferi in the northwestern US.

Mice and deer are the major reservoirs of B. burgdorferi. Ixodes ticks feed once in each of the three stages of their two-year life cycle. After hatching in the spring, larvae feed in summer, acquiring B. burgdorferi from their preferred host, the white-footed mouse. The following spring, the larvae develop into nymphs, which again feed off the white-footed mouse. The nymphs mature into adult ticks, which feed and mate in autumn and winter, usually on the white-tailed deer. B. burgdorferi is passed between ticks and their hosts. Humans can become accidental hosts during the spring and summer, when nymphs are actively feeding, through the deposition of organisms into the skin through tick saliva.

Management strategy

Routine antimicrobial prophylaxis or serologic testing after a tick bite is not recommended. Some experts recommend prophylaxis for patients bitten by I. scapularis ticks that have been attached over 36 hours if exposure occurred in an endemic area. This recommendation is based on evidence that a single 200 mg dose of doxycycline prevented 87% of Lyme infections if administered within 72 hours of tick removal. Accurate and detailed exposure history, however, is often unavailable. Those with a known tick exposure should be monitored for up to 30 days for the occurrence of skin lesions or fever. Cutaneous lesions or symptoms developing within one month after tick removal should prompt evaluation for early Lyme disease.

The best mode of preventing Lyme disease is avoidance of tick-infested areas. If tick exposure is unavoidable, then one should wear light-colored clothing and long pants tucked into socks to prevent ticks from finding exposed skin. Skin self-inspection within 36 hours of tick exposure and bathing within 2 hours of exposure have been associated with decreased risk of Lyme borelliosis. Daily inspection of the entire body, including the scalp, is recommended since attached ticks removed within 24–36 hours are unlikely to transmit B. burgdorferi. DEET-containing insect repellents provide added protection. Ixodes ticks are small: larvae are less than 1 mm in size and adult females are 2–3 mm in size. Attached ticks should be removed with tweezers by carefully pulling on the mouth apparatus close to the skin, taking care not to leave parts of the embedded tick behind.

Lyme disease generally occurs in stages, with different signs and symptoms at each stage. Therapeutic recommendations vary depending on the stage of disease and the presence of extracutaneous manifestations.

Early localized Lyme disease

The most common clinical manifestation of early Lyme disease is erythema migrans (EM). This characteristic skin lesion usually begins as an erythematous papule and develops into an expanding, erythematous, annular lesion with central clearing and distinct edge at the site of the tick bite and can be minimally tender. In most patients with Lyme, EM appears a median of 10 days after spirochete inoculation. The lesion may be accompanied by non-specific symptoms including fever, regional lymphadenopathy, arthralgias, fatigue, and headaches. About 75–80% of patients in the US who present with EM have a single primary lesion. Others can have secondary lesions due to hematogenous dissemination from the primary site. Untreated lesions usually fade within three to four weeks. Administration of doxycycline 100 mg twice daily, amoxicillin 500 mg three times daily, or cefuroxime axetil 500 mg twice daily for at least 14 days is recommended for early localized or early disseminated Lyme disease associated with EM. Doxycycline has the advantage of treating human granulocytic anaplasmosis caused by Anaplasma phagocytophilium, which also can be transmitted by I. scapularis. Doxycycline can cause photosensitivity and is contraindicated during pregnancy or breastfeeding and for children less than eight years old.

A rare skin manifestation of early Lyme infection described predominantly in Europe is Borrelial Lymphocytoma (BL). This solitary bluish-red nodule occurs at the site of a tick bite typically preceding or concomitantly with EM. Commonly involved sites are the ear lobes in children and near or on the nipple in adults. BL may develop within weeks to months after a tick bite and if untreated can persist for months to years. Treatment regimens used to treat EM can be used to treat BL.

Early disseminated Lyme disease

Early dissemination of the spirochete occurs via blood or lymphatics over several weeks in untreated infection. In this setting multiple annular skin lesions resembling primary EM can appear though these lesions are generally smaller. Other common symptoms include fever, lethargy, myalgias, headache, and mild neck stiffness. Patients may present with atrioventricular (AV) conduction disturbances, iritis or uveitis, aseptic meningitis (lymphocytic pleocytosis in CSF), cranial nerve palsies (notably facial nerve palsies), or peripheral radiculopathy. In adults, intravenous ceftriaxone 2 g daily for 14–28 days is recommended for early Lyme disease presenting with neurologic or advanced cardiac conduction abnormalities. Parenteral penicillin or cefotaxime are second-line agents. Temporary pacing may be required for patients with high-degree AV block (PR interval ≥ 0.30 seconds). Insertion of a permanent pacer is not necessary as conduction defects resolve spontaneously. Isolated facial nerve palsy and first degree AV block can be treated with oral doxycycline.

Late Lyme disease

Late Lyme disease can occur months to years after previously untreated or inadequately treated initial infection. Lyme arthritis is the most common manifestation of late Lyme disease, although decreasing in incidence due to improved recognition of early disease. Lyme arthritis is oligoarticular and presents as recurrent swelling of large joints, primarily the knees. Persistent swelling is atypical. Positive serologic testing is required to confirm the diagnosis and positive PCR results from synovial fluid strengthens the diagnosis.

Late neuroborreliosis is rare and can manifest as peripheral neuropathy, encephalomyelitis, or a subacute encephalopathy characterized by memory disturbances, mood alterations, and somnolence.

A rare dermatologic finding associated with late Lyme disease is acrodermatitis chronica atrophicans (ACA). ACA has been predominantly described in elderly female patients and has rarely been seen in the US, but is not infrequent in Europe due to its association with B. afzelii. ACA presents months to years after initial infection with a poorly demarcated area of violaceous discoloration and swelling of involved skin. These lesions usually involve the extensor surfaces of the extremities including the dorsum of hands. Over time the lesions becomes atrophic, with a characteristic hyperpigmented, hairless, translucent appearance. Involvement of peripheral nerves is not uncommon causing sensory neuropathy in addition to cutaneous abnormalities.

Lyme arthritis without neurologic symptoms can be treated with a 28-day oral regimen of either doxycycline 100 mg twice daily or amoxicillin 500 mg three times daily. Adults with evidence of concurrent neurologic involvement should receive intravenous ceftriaxone. Recurrent or persistent joint swelling after an oral regimen can be re-treated with another 28-day course of oral antimicrobials or with a two- to four-week parenteral regimen. Adults with late neurologic disease should be treated with a parenteral regimen for two to four weeks. Repeated or prolonged therapy is not recommended.

Specific investigations

Testing

Prospective study of serologic tests for Lyme disease.

Steere A, McHugh G, Damle N, Sikand V. Clin Inf Dis 2008; 47: 188–95.

Early Lyme disease is a clinical diagnosis with 80% of patients in endemic areas presenting with EM. Only one-third of patients presenting with EM and early Lyme disease have positive serology, but sensitivity increases during the convalescent phase. Two-step testing with ELISA and Western immunoblot remains the gold standard for diagnosing later stages of Lyme disease. In this study, over 90% of patients with disseminated disease and 100% of patients with late Lyme disease had positive two-step test results. The authors were also able to demonstrate increased sensitivity using a single step IgG C6 peptide ELISA. This test warrants further investigation in a broader patient population.

First-line therapies

Early localized disease (erythema migrans)*
image Doxycycline† 100 mg twice daily for 14 days A
image Amoxicillin 500 mg three times daily for 14 days A
image Cefuroxime axetil 500 mg twice daily for 14 days A
Early neurological (meningitis or radiculopathy)
image Ceftriaxone 2 g IV daily for 14 days B
image Penicillin G 18–24 million units IV daily (divided and dosed every 4 hours) for 14 days B
Cardiac disease including atrioventricular block
image Can be treated with oral or parenteral regimens recommended for early localized or early neurologic disease for 14 days‡ C
Lyme arthritis without neurologic involvement
image Doxycycline† 100 mg twice daily for 14 days B
image Amoxicillin 500 mg three times daily for 14 days B
Lyme arthritis with neurologic involvement
image Ceftriaxone 2 g IV daily for 14–28 days B
image Penicillin G 18—24 million units IV daily (divided and dosed every 4 hours) for 14–28 days B
Recurrent arthritis
image Re-treatment with a 28-day course of oral antibiotics D
Late neuroborreliosis
image Ceftriaxone 2 g IV daily for 14-28 days B
image Penicillin G 18–24 million units IV daily (divided and dosed every 4 hours) for 14–28 days B
Acrodermatitis chronic atrophicans
image Doxycycline 100 mg twice daily for 21 days C
image Amoxicillin 500 mg three times daily for 21 days C
image Cefuroxime axetil 500 mg twice daily for 21 days D

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*Level B recommendation for Borrelia Lymphocytoma and early Lyme disease with isolated cranial nerve palsy.

†Doxycycline is contraindicated in pregnancy and in children <8 years old.

‡Initial treatment with parenteral regimen recommended in hospitalized patients.

Second-line therapies

Early localized disease
image Erythromycin 250 mg orally four times daily for 14 days B
image Azithromycin 500 mg daily for 7 days B
Neurologic involvement or advanced cardiac conduction block
image Doxycycline 100 mg twice a day for 10–28 days B

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Second-line therapies are to be used in the setting of contraindication to first-line treatments (e.g., severe allergy).

Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease.

Nadelman RB, Luger SW, Frank E, Wisniewski M, Collins JJ, Wormser GP. Ann Intern Med 1992; 117: 273–80.

A randomized, multicenter, investigator-blinded trial treated 123 patients with EM for 20 days with either cefuroxime axetil 500 mg twice daily (n = 63) or doxycycline 100 mg twice daily (n = 60). Cure or improvement was achieved in 51 of 55 (93%) evaluable patients treated with cefuroxime axetil and in 45 of 51 (88%) patients treated with doxycycline. At one year post treatment, the percentage of patients who achieved a satisfactory outcome was comparable between the two groups. Cefuroxime was associated with more diarrhea than was doxycycline and is more expensive than doxycycline or amoxicillin.

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