Lyme borreliosis

Early Localized Lyme Disease

The most common clinical manifestation of early Lyme disease is erythema migrans (EM). This characteristic skin lesion occurs at the site of the bite a median of 10 days after inoculation, beginning as an erythematous papule and evolving into an expanding annular patch with a distinct edge. Although central clearing of erythema leading to a bullseye or targetoid appearance is characteristic, many lesions do not demonstrate this finding and absence of central clearing should not exclude an EM diagnosis. It is important to note that in individuals with darker skin, EM can appear as a bruise, hypo/hyperpigmentation without erythema, which may be misdiagnosed as cellulitis. The lesion may be accompanied by non-specific symptoms including fever, regional lymphadenopathy, arthralgias, fatigue, and headache. About 75% of patients with Lyme disease in the USA are diagnosed during the early localized Lyme stage with a single primary lesion. Untreated lesions usually fade within 3–4 weeks. In the southeast and south central areas of the USA, the southern tick-associated rash illness (STARI) can be indistinguishable from Lyme’s EM.

Administration of doxycycline 100 mg twice daily for 10 days, or, amoxicillin 500 mg three times daily, or cefuroxime axetil 500 mg twice daily for 14 days is recommended for early localized or early disseminated Lyme disease associated with EM. Doxycycline has the advantage of also treating human granulocytic anaplasmosis caused by Anaplasma phagocytophilum , which can be cotransmitted by I. scapularis bites . Doxycycline can cause photosensitivity and is contraindicated during pregnancy or breastfeeding. Traditionally it was also contraindicated for children; however, the American Academy of Pediatrics has now supported courses less than 3 weeks for children younger 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. Multiple annular skin lesions resembling primary EM can arise when spirochetes are deposited at skin sites remote from the initial bite – notably these lesions are generally smaller. However, it is important to keep in mind that multiple areas of EM are most commonly associated with spirochetemia, rather than multiple tick bites. Other common symptoms include fever, lethargy, myalgias, headache, and neck stiffness. Patients may present with atrioventricular (AV) conduction disturbances, iritis or uveitis, aseptic meningitis (lymphocytic pleocytosis in cerebral spinal fluid with normal glucose), cranial nerve palsies (notably facial nerve palsies), or peripheral radiculopathy. In adults, intravenous ceftriaxone 2 g daily for 14–21 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 usually resolve with medical treatment alone. 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. Positive polymerase chain reaction (PCR) results from synovial fluid can strengthen the diagnosis (sensitivity ranges 71%–100%).

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 USA but is more common in European patients 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 become atrophic, with a characteristic hyperpigmented, hairless, translucent appearance. Involvement of peripheral nerves can also result in sensory neuropathy.

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 2–4-week parenteral regimen. Adults with late neurologic disease should be treated with a parenteral regimen for 2–4 weeks. Repeated or prolonged therapy is not recommended.

Diagnosis

In cases of early Lyme disease that present as skin lesions consistent with EM with potential exposure to infectious ticks in a Lyme disease-endemic area, clinical diagnosis is recommended. Serology (around 40% sensitivity) and skin biopsy culture (40%–60% sensitivity) is not recommended to confirm skin lesions as EM. In non-cutaneous disease or in the presence of skin lesions that are suggestive of but atypical for EM, if the clinical history and physical examination support Lyme disease as a leading diagnosis, then testing is recommended. Traditionally, two-step testing with enzyme-linked immunosorbent assay (ELISA) and Western immunoblot was the gold standard for diagnosing later stages of Lyme disease. In 2019, the Centers for Disease Control and Prevention (CDC) updated the two-test methodology to using a sensitive enzyme immunoassay (EIA) or immunofluorescence assay (IFA) as the first test, then a second EIA as the second test, rather than the Western immunoblot assay. This is now called the modified 2-tier test (MTTT).

Posttreatment Symptoms

Persistent arthritic complaints appear to be immunologically mediated and are most common in individuals with the HLA-DR4 haplotype. Research studies have not consistently demonstrated microbiological persistence of Borrelia in patients with symptoms following completion of treatment for Lyme. Moreover, prolonged or multiple courses of antimicrobials are unhelpful and may be harmful. Symptomatic treatment with non-steroidal agents, intraarticular corticosteroids, disease modifying antirheumatic drugs, or, in severe non-remitting cases, arthroscopic synovectomy may provide relief.

Reinfection and Vaccination

Patients treated for early Lyme disease, specifically EM, do not develop protective immunity and if reexposed may become reinfected. The clinical presentation associated with reinfection is similar to primary infection. At this time there is no vaccine available to protect against Lyme disease.