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LYME DISEASE—A DIAGNOSTIC CHALLENGE

LYME DISEASE—A DIAGNOSTIC CHALLENGE

Bibliography

Lyme disease is a multisystem disease with protean manifestations. The illness was brought to attention in 1977 when it was thought that the “juvenile rheumatoid arthritis” of a group of children in Lyme, Connecticut, had an infectious cause. Subsequent studies identified Ixodes ticks as vectors of the disease, and in 1982, a spirochete, now called Borrelia burgdorferi, was isolated from Ixodes scapularis (formerly Ixodes dammini). Features of the illness were recognized in Europe early in this century.
Lyme disease is the most commonly reported tick-borne disease in the United States. Cases have occurred in all states except Alaska, Arizona, Colorado, Montana, Nebraska, and New Mexico, although the disease is regional, with more than 90% of cases reported from the northeastern states, Maryland, Wisconsin, Missouri, and California. The disorder has also been noted in Europe, China, Japan, Australia, and the former Soviet Union. Cases have been reported worldwide except in the Antarctic.
Although the disorder is not rare, confusion exists for most clinicians regarding the diagnosis. For every case of Lyme disease that is diagnosed, it is estimated that 50 to 100 serologic tests for Lyme disease are performed. A number of factors have contributed to the diagnostic dilemma for clinicians and confusion for patients. First, unlike most bacterial infections, Lyme disease is not diagnosed by isolation of the etiologic agent or demonstration of the antigen or organism by special stains in tissue. Second, the clinical features are protean and may mimic those of several other diseases. The pathognomonic skin lesion, erythema migrans, which develops at the site of the tick bite, is absent in one third of patients. Third, confusion exists regarding the interpretation of a positive or negative result of the serologic test for Lyme disease antibody. Clinicians believe that a positive Lyme disease test result alone confirms the diagnosis. A positive Lyme serology may be a false-positive because of cross-reacting antibodies; alternatively, it may indicate past infection with B. burgdorferi or suggest active infection. Elevated antibody titers may persist for years with or without therapy and do not indicate the presence of an active infection that requires antimicrobial therapy. A false-negative serologic test result may be seen early in the illness because the antibody response may not appear until 3 to 6 weeks after the tick bite. Antimicrobial therapy can also diminish the antibody response, resulting in a false-negative serologic test result. Finally, confusion exists regarding how to manage a patient who reports a tick bite and is concerned about the development of Lyme disease.
Lyme disease can be classified into early and late infection. Early infection can be further subdivided into localized infection (stage 1) or disseminated infection (stage 2). Erythema migrans is the hallmark of early localized disease. The rash usually occurs 3 to 32 days (median, 7 days) after the initial tick bite. The rash is described as an annular, expanding, erythematous lesion with central clearing that is at least 5 cm in diameter. The center of the lesion may become vesicular and necrotic or remain erythematous. Secondary annular skin lesions occur in half the patients. These lesions resemble those of erythema migrans. The skin lesions usually fade within 3 to 4 weeks, even if untreated. Fever and minor constitutional symptoms, such as malaise and fatigue or regional lymphadenopathy, may accompany the classic skin rash. It is extremely difficult to diagnose Lyme disease in a patient with flulike symptoms alone without a rash because the serology is usually negative at this time.
Manifestations of early disseminated disease may involve the nervous, cardiovascular, or musculoskeletal system. The spectrum of neurologic disease includes lymphocytic meningitis; cranial neuritis, such as Bell’s palsy; radiculoneuropathy; or, rarely, encephalomyelitis. Bell’s palsy is the most common cranial neuropathy. Headache, paresthesia, and a mild stiff neck alone are not accepted as criteria for the diagnosis of neurologic disease. Symptoms of musculoskeletal involvement can include migratory arthralgias, muscle and bone pain, and transient arthritis affecting the large joints, such as the knees. The arthritis usually begins 6 months after onset. Cardiac manifestations begin about 2 to 6 weeks after onset and include atrioventricular block and, less often, myocarditis or pericarditis. Syncope caused by cardiac conduction abnormality may be the presenting complaint. Late or persistent infection is manifested as a chronic arthritis, lasting a year or more, involving the knees; neurologic disorders, such as an encephalomyelitis; and a localized cutaneous disorder, acrodermatitis chronica atrophicans. Ocular abnormalities may occur as part of early disseminated disease.
Because it is difficult to culture the spirochete from most patients with Lyme disease, the diagnosis must rely heavily on the clinical presentation and epidemiologic clues. The diagnosis is often a challenge because laboratory support depends on detection of an immune response to the organism, which has the limitations already noted. Current methods of testing use mainly an enzyme-linked immunosorbent assay (ELISA) and Western blot (immunoblot) test. Specific IgM antibodies against the organism appear about 1 month after the onset, peak at 2 months, and then decline. Specific IgG antibodies are detectable in the second month and may remain elevated for life. Antibody levels decline with treatment but usually persist indefinitely. Antibody levels should not be monitored to indicate success or failure of therapy. Similarly, the presence of antibodies may indicate a previous infection, with the patient’s acute symptoms having another cause. Serologic testing is not helpful to diagnose recurrent disease.
Immunoblot testing (Western blot) can support the diagnosis of Lyme disease, but a negative test result does not exclude the disorder. In early disease, an antibody response to a flagellar protein (flagellin) and to a fragment of this protein, designated as 41G, develops in some patients. In late disease, the antibody response is directed to outer-surface proteins A and B in addition to the flagellar proteins. Again, cross-reacting antibodies directed against other spirochetes can confuse the picture, and the clinician should discuss with the laboratory personnel the criteria used to classify a Western blot test as positive. Some laboratories require the presence of four or five bands on the Western blot to consider the result positive. Serologic tests for Lyme disease can easily be misinterpreted. A two-step approach is advised. The first step is to perform an ELISA or indirect immunofluorescence test. A positive or equivocal result should be followed by a Western blot assay. This second test is supplemental rather than confirmatory because of suboptimal specificity. A negative test result does not exclude the diagnosis, and another sample should be obtained 1 month later.
In addition to antibody responses to infection, specific cellular immune responses occur. In a group of seronegative patients with Lyme disease, a T-cell proliferative assay may be useful to demonstrate exposure to B. burgdorferi. However, this test is still confined to research purposes, and the results must be interpreted with caution. Other laboratory methods, such as antigen detection and the polymerase chain reaction (PCR), are still experimental. In one report in which material obtained by 2-mm skin biopsy was used, the sensitivity of the PCR was about 60%. These new methods may prove to be invaluable considering the limitations of making the diagnosis by means of the various antibody tests.
The topic of Lyme disease has generated numerous questions from both clinicians and patients:

1.
How long must a tick be attached to transmit the disease? In experimental studies, it is unlikely for ticks attached for less than 48 hours to transmit disease. It is important to prevent tick bites by using appropriate insect repellents and protective clothing. Ticks should be removed with a forceps.

2.
How would you interpret a positive ELISA or a positive immunoblot test? A positive test result indicates possible exposure to B. burgdorferi but does not confirm active infection. The diagnosis of Lyme disease is a clinical one supported by laboratory studies.

3.
Does a negative serologic test result for Lyme disease exclude the diagnosis? No. False-negative results occur mainly during the first several weeks of the illness. Late infection is usually associated with a positive serologic test result. Rarely, patients will have a negative serologic test for Lyme antibody with late infection and have a positive T-cell response to B. burgdorferi. The specificity of this test is unclear, and it is not recommended for diagnosis at present.

4.
What are the causes of a false-positive serologic test result for Lyme antibody? Causes of a false-positive Lyme serology include systemic lupus erythematosus, rheumatoid arthritis, Rocky Mountain spotted fever, infectious mononucleosis, and various spirochetal diseases, such as syphilis, relapsing fever, and periodontal disease. Patients with Lyme disease will have a negative result on a nontreponemal test for syphilis, such as the Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin circle card test (RPR-CT), and may have a false-positive result on the fluorescent treponemal antibody absorption test (FTA-ABS) test. Another problem that should always be considered is the patient with an asymptomatic B. burgdorferi infection and a positive Lyme serologic test. In this situation, the patient’s symptoms may be falsely attributed to Lyme disease because of the positive antibody test result, and the correct diagnosis is missed.

5.
Does Lyme disease cause chronic fatigue syndrome? The diagnosis of chronic fatigue syndrome depends on excluding other diseases. The diagnosis of Lyme disease should not be searched for as a cause of fatigue unless a patient has epidemiologic evidence to suggest infection with B. burgdorferi, plus other clinical manifestations of Lyme disease. Rarely, fibromyalgia may develop in patients with treated Lyme disease. In patients with fibromyalgia triggered by prior Lyme disease, there is no evidence that antimicrobial therapy alters the course of the illness.

6.
Is there a role for prolonged antimicrobial therapy in a patient with Lyme disease? Although the optimal therapy for Lyme disease is unknown, it appears that antimicrobials usually should be administered for 3 weeks to eradicate the organism. There is no evidence that antimicrobial therapy for longer than 30 days, even for patients with Lyme arthritis, provides any advantage. After therapy is started, patient symptoms may worsen because of a Jarisch-Herxheimer reaction. Oral therapy should be adequate for most infections, and IV therapy should be reserved for patients with well-documented chronic disease, such as Lyme arthritis, or disseminated disease with major organ involvement, such as Lyme carditis or Lyme meningitis.

7.
How should you manage someone in an endemic area who is asymptomatic and has a positive Lyme serology? In endemic areas, rates of Lyme seropositivity may be as high as 22.5%. No data are available to indicate whether late complications of Lyme disease will develop in patients who are asymptomatic. The role of antimicrobials in this setting is unclear.

8.
What is the role for prophylactic antimicrobials to prevent Lyme disease after the bite of a deer tick? The risk for acquiring Lyme disease, even in an endemic area, after a deer tick bite is low. Therefore, prophylactic antimicrobials are not usually indicated. One exception might be a pregnant patient, but this issue has not been studied.

9.
Is there a risk for transmitting B. burgdorferi infection to the fetus during pregnancy? Although there is a potential for maternal-to-fetal transmission of B. burgdorferi during pregnancy, the risk appears to be extremely low. There is no need to screen for Lyme antibodies in asymptomatic women during pregnancy. However, suspected or documented cases of Lyme disease should be treated during pregnancy. Controlled studies are needed to assess the risk to the fetus associated with maternal Lyme disease.

10.
After a patient with Lyme disease is treated, should antibody titers be monitored to assess cure? Antimicrobial therapy usually causes a decline in antibody levels against B. burgdorferi. However, the patient usually remains seropositive indefinitely, and repeated serologic testing is not indicated.
Despite a tremendous increase in our understanding of Lyme disease, controversies and confusion still exist regarding this illness. It is hoped that better answers to many questions concerning Lyme disease will be forthcoming. (N.M.G.)
Bibliography
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Half of the early cases and about 10% of the late cases recalled a tick bite. In the Midwest, onset of early disease occurred mainly from June through November.
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A false-positive rate of 2% to 27% was noted. Interlaboratory results were highly variable.
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Guidelines for diagnosis and treatment from the American Academy of Pediatrics (see also Canadian Pediatric Society. How to diagnose and treat Lyme disease in children. Can Med Assoc J 1992;147:169).
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A marked variability was noted in the results of serologic testing between different laboratories, with sensitivities ranging from 13% to 73%.
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Atrioventricular block usually resolves within 6 weeks with antimicrobial therapy.
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Use a two-test approach for serologic diagnosis. If results of the enzyme immunoassay are positive, then obtain a Western immunoblot. (Order immunoglobulin M immunoblot if the illness has been present less than 1 month; otherwise obtain an immunoglobulin G immunoblot.)
Dattwyler RJ, et al. Seronegative Lyme disease: dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 1988;319:1441.
A test that measures T-cell blastogenic response to B. burgdorferi may be helpful in the diagnosis of the rare patient with clinical evidence of chronic Lyme disease and a negative serology.
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Fibromyalgia may develop in treated patients with Lyme disease; antimicrobials are not indicated for these patients.
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With the Western blot test, the sensitivity varied between 32% and 83%, and the specificity was 95% to 100%.
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A test measuring the T-cell proliferative response to B. burgdorferi antigens had a sensitivity of 45% and specificity of 95% in a small group of patients with late Lyme disease.
Dumler JS. Is human granulocytic ehrlichiosis a new Lyme disease? Review and comparison of clinical, laboratory, epidemiological, and some biological features. Clin Infect Dis 1997;25(Suppl 1):S43–S47.
Although ehrlichiosis and Lyme disease are both transmitted by deer ticks (Ixodes scapularis), leukopenia, thrombocytopenia, and abnormal hepatic transaminases occur with the former and are usually absent in Lyme disease.
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A typical lesion of erythema migrans is annular, erythematous, and at least 5 cm in diameter, and it begins to develop 3 to 30 days after a tick bite.
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Measurement of antibodies to outer-surface proteins A and B, flagellin, and region of flagellin (41G) from B. burgdorferi with an immunoblot and ELISA was useful in the serodiagnosis of Lyme disease.
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Overuse of serologic testing and prophylactic antibiotic therapy.
Gerber MA, Shapiro ED. Diagnosis of Lyme disease in children. J Pediatr 1992;121: 157.
A skin lesion that appears immediately after a tick bite, resolves within 1 to 2 days without appropriate antimicrobial therapy, and is less than 5 cm is unlikely to be erythema migrans.
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Diagnosis should be based on the history and clinical findings, with the laboratory providing supporting evidence.
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PCR on cerebrospinal fluid is a useful method to detect B. burgdorferi. This test appears to be an alternative to the measurement of intrathecal production of specific Lyme antibody.
Kuiper H, et al. Absence of Lyme borreliosis among patients with presumed Bell’s palsy. Arch Neurol 1992;49:940.
Lyme disease was identified in 6% of patients with peripheral facial palsy, compared with a rate of 4.5% in controls. Screening for Lyme disease is not indicated in this setting unless other evidence suggests the diagnosis.
Lawson JP, Rahn DW. Lyme disease and radiologic findings in Lyme arthritis. AJR Am J Roentgenol 1992;58:1065.
The most frequent abnormality is a joint effusion involving the knee. Loss of cartilage occurs in about 25% of patients with chronic Lyme arthritis.
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In a small study, B. burgdorferi was identified in the cerebrospinal fluid of 67% of patients with early disseminated disease when a PCR assay was used.
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Serologic testing should not be the sole criterion used to make the diagnosis of Lyme disease because of wide variability in the test results among laboratories.
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A review of the cutaneous lesions. Erythema migrans occurs in about 75% of patients with Lyme disease.
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A 20-day course of cefuroxime axetil (500 mg twice daily) or doxycycline (100 mg three times daily) was effective in patients with early Lyme disease.
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Use of a quantitative Western blot test was helpful in establishing the diagnosis. Patients with secondary syphilis had positive results on immunoblots.
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Of a group of referred patients with presumptive Lyme disease, only 21% met criteria for active Lyme disease. Most positive results on serologic tests for Lyme disease are false-positives.
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The sensitivity of PCR for the detection of B. burgdorferi in skin biopsy specimens was about 60%. The yield was similar when culture was used.
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In an endemic area, prophylactic amoxicillin is not indicated to prevent Lyme disease after a deer tick bite.
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Lyme disease was diagnosed in only 37% of patients referred for evaluation. Fibromyalgia was common.
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Review.
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Lyme arthritis usually responds to a 1-month course of antibiotics—doxycycline, amoxicillin, or ceftriaxone (see also Steere AC. Diagnosis and treatment of Lyme arthritis. Med Clin North Am 1997;81:179–194).
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The spectrum of disease in untreated patients with Lyme arthritis includes intermittent episodes of arthritis (64%), arthralgias alone (23%), and chronic arthritis (14%).
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Erythema migrans is illustrated. Multiple annular secondary skin lesions developed in half the patients.
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Erythema migrans responded to antimicrobial therapy in 5 days with and in 10 days without treatment. Major late complications did not occur in patients who were treated with tetracycline.
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Measurement of intrathecal antibody production, most commonly IgA, was useful in the diagnosis of Lyme neuroborreliosis. A negative study result, particularly in patients with peripheral nervous system involvement, does not exclude the diagnosis.
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For erythema migrans, doxycyline, amoxicillin, or cefuroxime axetil is recommended.
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Although Lyme disease is the most common tick-borne disease in North America, laboratory testing is indicated only if the pretest probability is .20 or higher (see also American College of Physicians. Guidelines for laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997;127:1106–1108).
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A metaanalysis of clinical trials failed to establish the efficacy of antibiotics as prophylaxis for tick bites.
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Ceftriaxone is the drug of choice for neuroborreliosis.
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Culture of material obtained by a 2-mm skin biopsy and fluid from a technique called cutaneous needle lavage yielded B. burgdorferi. Skin biopsy culture was more sensitive than lavage culture (74% vs. 40%).

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