Red Book 28e

Lyme Disease

Clinical Manifestations

(Lyme Borreliosis, Borrelia burgdorferi Infection)

Clinical Manifestations of Lyme disease are divided into 3 stages: early localized, early disseminated, and late disease. Early localized disease is characterized by a distinctive rash, erythema migrans , at the site of a recent tick bite. Erythema migrans is the most common manifestation of Lyme disease in children; only a small proportion of children are diagnosed with early disseminated or late Lyme disease without a history of erythema migrans. Erythema migrans begins as a red macule or papule that usually expands over days to weeks to form a large, annular, erythematous lesion that typically increases in size to 5 cm or more in diameter, sometimes with partial central clearing. The lesion usually is painless and not pruritic. Localized erythema migrans can vary greatly in size and shape and may have vesicular or necrotic areas in its center and can be confused with cellulitis. Fever, malaise, headache, mild neck stiffness, myalgia, and arthralgia often accompany the rash of early localized disease.

Approximately 15% of patients with Lyme disease come to medical attention with early disseminated disease, most commonly multiple erythema migrans. This rash usually occurs several weeks after an infective tick bite and consists of secondary annular, erythematous lesions similar to, but usually smaller than, the primary lesion. These lesions reflect spirochetemia with cutaneous dissemination. Other common manifestations of early disseminated illness (that may occur with or without rash) are palsies of the cranial nerves (especially cranial nerve VII), lymphocytic meningitis, and conjunctivitis. Systemic symptoms, such as arthralgia, myalgia, headache, and fatigue, also are common during the early disseminated stage. Carditis, which usually manifests as various degrees of heart block, occurs rarely in children. Occasionally, people with early Lyme disease have concurrent human granulocytic anaplasmosis or babesiosis, transmitted by the same tick, which may contribute to symptomatology.

Late disease is characterized most commonly by relapsing arthritis that usually is pauciarticular and affects large joints, particularly knees. Arthritis can occur without a history of earlier stages of illness (including erythema migrans). Peripheral neuropathy and central nervous system manifestations also can occur rarely during late disease. Children who are treated with antimicrobial agents in the early stage of disease almost never develop late disease.

Because congenital infection occurs with other spirochetal infections, there has been concern that an infected pregnant woman could transmit Borrelia burgdorferi to her fetus. No causal relationship between maternal Lyme disease and abnormalities of pregnancy or congenital disease caused by B burgdorferi has been documented conclusively. No evidence exists that Lyme disease can be transmitted via human milk.


In the United States, infection is caused by the spirochete B burgdorferi sensu stricto.


Lyme disease occurs primarily in 3 distinct geographic regions of the United States. Most cases occur in southern New England and in the eastern mid-Atlantic states. The disease also occurs, but with lower frequency, in the upper Midwest, especially Wisconsin and Minnesota, and less commonly on the West Coast, especially northern California. The occurrence of cases in the United States correlates with the distribution and frequency of infected tick vectors-Ixodes scapularis in the east and Midwest and Ixodes pacificus in the west. Reported cases from states without known enzootic risks may have been acquired in states with endemic infection or may be misdiagnoses resulting from false-positive serologic test results. Rash similar to erythema migrans has been reported in states without endemic infection; however, the Etiology of this condition remains unknown. Most cases of early disease occur between April and October; more than 50% of cases occur during June and July. People of all ages may be affected, but incidence in the United States is highest among children 5 through 9 years of age and adults 45 through 54 years of age.

The incubation period from tick bite to appearance of single or multiple erythema migrans lesions ranges from 1 to 32 days with a median of 11 days. Late manifestations can occur months to years after the tick bite.

Endemic Lyme disease transmitted by ixodid ticks occurs in Canada, Europe, states of the former Soviet Union, China, and Japan. The primary tick vector in Europe is Ixodes ricinus , and the primary tick vector in Asia is Ixodes persulcatus . Clinical Manifestations of infection vary somewhat from manifestations seen in the United States, probably because of different genomospecies of Borrelia .

Diagnostic Tests

During the early stages of Lyme disease, the diagnosis is best made clinically by recognizing the characteristic rash, a singular lesion of erythema migrans, because antibodies against B burgdorferi are not detectable in most people within the first few weeks after infection. During the first 4 weeks of infection, seroDiagnostic Tests are insensitive and are not recommended generally. Although cultures of a biopsy specimen of the perimeter of the skin lesion often yield the organism, cultures of Borrelia species (which require special media) are not available commercially and are not recommended. Diagnosis in patients with early disseminated disease who have multiple lesions of erythema migrans also is made clinically. Diagnosis of early disseminated disease without rash or late Lyme disease should be made on the basis of clinical findings and serologic test results. Some patients who are treated with antimicrobial agents for early Lyme disease never develop antibodies against B burgdorferi ; they are cured and are not at risk of late disease. Most patients with early disseminated disease and virtually all patients with late disease have antibodies against B burgdorferi . Once such antibodies develop, they persist for many years and perhaps for life. Consequently, tests for antibodies should not be used to assess the success of Treatment. The results of serologic tests for Lyme disease should be interpreted with careful consideration of the clinical setting and the quality of the testing laboratory.

A 2-step approach is recommended for serologic diagnosis of B burgdorferi . First, a quantitative screening test for serum antibodies should be performed using a sensitive enzyme immunoassay (EIA) or immunofluorescent antibody assay (IFA). Serum specimens that yield positive or equivocal results then should be tested by a standardized Western immunoblot for presence of antibodies to B burgdorferi ; serum specimens that yield negative results by EIA or IFA should not be tested further by immunoblot. Immunoblot test should not be performed if EIA test result is negative or instead of an EIA; positive immunoblot results likely would not be attributable to Lyme disease. When testing to confirm early disseminated disease without rash, immunoglobulin (Ig) G and IgM immunoblot assays should be performed. To confirm late disease, only an IgG immunoblot assay should be performed, because false-positive results may occur with the IgM immunoblot. In people with symptoms lasting longer than 1 month, a positive IgM test result alone (ie, negative IgG test) is likely to represent a false-positive result and should not be the basis on which to diagnose Lyme disease. A positive result of an IgG immunoblot test requires detection of antibody ("bands") to 5 or more of the following: 18, 23/24, 28, 30, 39, 41, 45, 60, 66, and 93 kDa polypeptides. A positive test result of IgM immunoblot requires detection of antibody to at least 2 of the 23/24, 39, and 41 kDa polypeptides. Two-step testing is needed, because EIA and IFA may yield false-positive results because of the presence of antibodies directed against spirochetes in normal oral flora that cross-react with antigens of B burgdorferi or to cross-reactive antibodies in patients with other spirochetal infections (eg, syphilis, leptospirosis, relapsing fever), certain viral infections (eg, varicella, Epstein-Barr virus), or certain autoimmune diseases (eg, systemic lupus erythematosus).

A licensed serologic test that detects antibody to a peptide of the immunodominant conserved region of the variable surface antigen vlsE of B burgdorferi appears to have equivalent specificity and sensitivity compared with the 2-step protocol. Polymerase chain reaction (PCR) testing (using a laboratory with excellent quality procedures) has been used to detect B burgdorferi DNA in joint fluid. Urinary antigen detection has no role in diagnosis.

Suspected central nervous system Lyme disease can be confirmed by demonstration of intrathecal production of antibodies against B burgdorferi . However, interpretation of results of antibody tests of cerebrospinal fluid is complex, and physicians should seek the advice of a specialist experienced in management of patients with Lyme disease to assist in interpreting results.

The widespread practice of ordering serologic tests for patients with nonspecific symptoms, such as fatigue or arthralgia, who have a low probability of having Lyme disease or because of parental pressure, is discouraged. Almost all positive serologic test results in these patients are false-positive results. In areas with endemic infection, subclinical infection and seroconversion also can occur, and the patient's symptoms merely are coincidental. Patients with acute Lyme disease almost always have objective signs of infection (eg, erythema migrans, facial nerve palsy, arthritis). Nonspecific symptoms commonly accompany these specific signs but almost never are the only evidence of Lyme disease.


Consensus practice guidelines for assessment, Treatment, and prevention of Lyme disease have been published by the Infectious Diseases Society of America. Care of children should follow recommendations in Table 3.33. Antimicrobial therapy for nonspecific symptoms or for asymptomatic seropositivity or by routes of administration or durations not specified in Table 3.33 is discouraged. Use of alternative diagnostic approaches or therapies recommended by other groups or people also is discouraged.

Table 3-33

Early Localized Disease

Doxycycline is the drug of choice for children 8 years of age and older and, unlike amoxicillin, also treats patients with anaplasmosis. For children younger than 8 years of age, amoxicillin is recommended. For patients who are allergic to penicillin, the alternative drug is cefuroxime. Erythromycin and azithromycin are less effective. Most experts treat people with early Lyme disease for 14 to 21 days.

Treatment of erythema migrans almost always prevents development of later stages of Lyme disease. Erythema migrans usually resolves within several days of initiating Treatment, but other signs and symptoms may persist for several weeks, even in successfully treated patients.

Early Disseminated and Late Disease

Orally administered antimicrobial agents are recommended for treating multiple erythema migrans and uncomplicated Lyme arthritis. Oral agents also are appropriate for Treatment of facial nerve palsy without Clinical Manifestations of meningitis; lumbar puncture is not indicated. If symptoms or signs of other central nervous system involvement, such as meningitis or raised intracranial pressure, are present, lumbar puncture is performed. If cerebrospinal fluid pleocytosis is found, parenterally administered antimicrobial therapy is indicated. Up to one third of patients with arthritis have persistence of synovitis and joint swelling at the conclusion of antimicrobial therapy, which almost always resolves without repeating the course of antimicrobial therapy. Some experts would treat a patient who has recurrent or persistent arthritis after Treatment with one course of oral antimicrobial therapy with another course of oral antimicrobial therapy. Central nervous system infection should be treated with parenterally administered antimicrobial therapy. The optimal duration of therapy for manifestations of early disseminated or late disease is not well established, but there is no evidence that children with any manifestation of Lyme disease benefit from prolonged courses of orally or parenterally administered antimicrobial agents. Accordingly, the maximum duration of a single course of therapy is 4 weeks (see Table 3.33).

The Jarisch-Herxheimer reaction (an acute febrile reaction accompanied by headache, myalgia, and an aggravated clinical picture lasting less than 24 hours) can occur when therapy is initiated. Nonsteroidal anti-inflammatory agents may be beneficial, and the antimicrobial agent should be continued.


Tetracyclines are contraindicated. Otherwise, therapy is the same as recommended for nonpregnant people.

Isolation of the Hospitalized Patient

Standard precautions are recommended.

Control Measures


see Prevention of Tickborne Infections .


Many people who seek medical attention for a tick bite have been bitten by a species of tick that does not transmit Lyme disease, or the recovered material is not a tick. The overall risk of infection with B burgdorferi after a recognized deer tick bite is less than 1% and, even in areas with highly endemic rates of infection, is sufficiently low that prophylactic antimicrobial Treatment is not indicated routinely for most people. People bitten by an ixodid tick in areas with low incidence of Lyme disease should not receive chemoprophylaxis. The risk is extremely low after attachment (eg, a flat, nonengorged deer tick is found) and is higher after engorgement, especially if a nymphal deer tick has been attached for at least 72 hours. Analysis of the tick for spirochete infection has a poor predictive value and is not recommended. On the basis of a study of doxycycline for prevention of Lyme disease after a deer tick bite, some experts recommend a single 200-mg dose (4.4 mg/kg for body weight less than 45 kg) of doxycycline for people 8 years of age and older who have been bitten in an area with hyperendemic infection (ie, local rate of infection of these ticks with B burgdorferi is 20% or greater) who have found an engorged deer tick, especially if the suspected duration of attachment is 72 hours or longer and prophylaxis can be started within 72 hours after the tick was removed. Data are insufficient to recommend amoxicillin prophylaxis.

Blood Donation

Patients with active disease should not donate blood, because spirochetemia occurs in early Lyme disease. Patients who have been treated for Lyme disease can be considered for blood donation.


A Lyme disease vaccine was licensed by the US Food and Drug Administration on December 21, 1998, for people 15 to 70 years of age but was withdrawn in early 2002 and no longer is available.


a . For patients who are allergic to penicillin, cefuroxime and erythromycin are alternative drugs.

b . Tetracyclines are contraindicated in pregnancy.

c . Corticosteroids should not be given.

d . Treatment has no effect on the resolution of facial nerve palsy; its purpose is to prevent late disease.

e . Arthritis is not considered persistent or recurrent unless objective evidence of synovitis exists at least 2 months after Treatment is initiated. Some experts administer a second course of an oral agent before using an IV-administered antimicrobial agent.

f . Ceftriaxone should be administered IV for Treatment of meningitis or encephalitis.

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 . 2006;43(9):1089-1134  [PMID:17029130]

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