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Lyme Disease: Who Should Be Tested and What Test Should Be Ordered?

May 2013

Lyme disease is a tick-borne illness that is endemic in certain areas of the United States, including the Northeast and Upper Midwest. It is caused by the spirochete Borrelia burgdorferi. When evaluating a patient with suspected Lyme disease, the diagnosis is often clinical, and is based on symptoms and objective clinical findings. The most characteristic manifestation is that of erythema migrans, also known as a target lesion or bull’s-eye rash. Erythema migrans is believed to occur in 60% to 75% of patients with Lyme disease. Other clinical findings may include facial palsy, atrioventricular block, or arthritis.

In several situations, laboratory testing is not recommended. When a patient presents with an appropriate exposure history and a “classic” erythema migrans rash, it is typically recommended to bypass laboratory testing and treat the patient according to approved guidelines.1 In addition, if a patient lacks symptoms, an appropriate exposure history, or is from a nonendemic region and has not recently visited an endemic area, laboratory testing is not recommended. Indiscriminate testing can result in a diagnostic dilemma and confusion on the part of both physician and the patient.

The signs and symptoms of Lyme disease are often nonspecific and may be indistinguishable from other infectious or noninfectious conditions, so the diagnosis can be difficult. If the patient does not have the characteristic Lyme disease rash, but has been outdoors where Lyme disease is common, laboratory tests to detect antibodies against the bacteria may be used to help confirm the diagnosis. These tests are most reliable when performed 2 to 4 weeks after an infection, when antibodies to the spirochete have had time to develop. Several standard methods can be used for testing when deemed appropriate. The most common approach for the laboratory diagnosis of Lyme disease is through the use of serology to detect IgG and IgM antibodies to Borrelia burgdorferi (LYME/9129 Lyme Disease Serology, Serum). It is important to remember that serology is generally insensitive during the acute phase of tick-borne infections (eg, first 7 days after symptom onset), so other testing, such as real-time PCR (PBORR/80574 Lyme Disease [Borrelia burgdorferi], Molecular Detection, PCR) on fresh tissue or synovial fluid may be recommended. Real-time PCR testing of whole blood is generally insensitive, and should not be used to rule out infection.

The Centers for Disease Control and Prevention (CDC) recommends a 2-step approach for the serologic diagnosis of Lyme disease. (See Figure). In the first tier of testing, the specimen is tested by a highly sensitive screening assay, such as an enzyme immunoassay (EIA) (LYME/9129 Lyme Disease Serology, Serum). If the result of the screening EIA is negative, no further testing is required with the present specimen. However, in the case of short disease duration, it may be beneficial to submit a follow-up specimen in 7 to 14 days if clinically indicated. If, on the other hand, the result of the screening assay is positive or equivocal, the specimen should be tested by Western blot for IgM- and IgG-class antibodies (LYWB/9535 Lyme Disease Antibody, Western Blot, Serum).

The criteria for interpreting Lyme Western blot results were established on serum samples, and should NOT be applied to cerebrospinal fluid (CSF) results. To assist in the diagnosis of neuroborreliosis, we recommend that a CSF and companion serum sample be submitted for Lyme antibody index testing, which is designed to assess whether intrathecal antibodies to Borrelia burgdorferi are present in CSF (CLYME/83856 Lyme Disease Serology, Spinal Fluid).

The Borrelia burgdorferi C6 enzyme immunoassay is used as the initial screen and the sensitivity of this assay may vary with the disease stage. During the acute stage of disease (first 1 to 2 weeks), sensitivity of this assay may be as low as 70% to 75%. In contrast, when testing is performed during stages 2 and 3 of Lyme disease, the sensitivity increases to greater than 90%. Early administration of antibiotics may weaken or delay the antibody response, and decrease the sensitivity of EIA. Western blot should be considered a supplementary, and not confirmatory, serologic approach, due to the potential for false positives and inter- and intra-laboratory result variability by this method. Testing by Western blot is not recommended in patients testing negative by screen EIA.

Similar to the screening C6 EIA test, the sensitivity of Lyme Western blot is also dependent on the stage of the disease when testing is performed. During stage 1, Western blot may demonstrate a sensitivity of only 20% to 50%, with the majority of antibody detected being of the IgM class. In stages 2 and 3 of the disease, the sensitivity of Western blot increases to 70% to 100%, and we typically observe a switch in prevalence of antibody to that of the IgG class. It is important to point out that although a positive IgM Western blot generally indicates recent infection, IgM-class antibodies may persist for months to years following infection in some cases, and because of this, a positive IgM does not always indicate recent, acute infection.

For those patients testing positive by IgM Western blot alone, the general recommendation is to repeat serologic testing on a new specimen after 14 to 21 days. Afterward, a positive test for IgG provides strong supportive evidence of infection.

Here are a few more points regarding Lyme Western blot. If testing is performed within 4 weeks of symptom onset, it is recommended that the results of both IgM and IgG Western blot be used in the interpretation. However, in patients with disease duration of greater than 1 month, the results of the IgM Western blot should not be considered diagnostic, and a positive IgM alone should not be used to diagnose infection due to the increased possibility of false-positive results during the later stages of disease.

In summary, laboratory diagnosis of Lyme disease is most commonly achieved by serologic testing, which should be limited to those persons with an appropriate exposure history and objective clinical findings. When serology is ordered, testing should be performed using the 2-step approach as recommended by the CDC, in which specimens are first tested by a highly sensitive screening method, such as EIA, with all screen-positive or equivocal specimens being tested by Western blot. The results of Lyme serology should be used to support a clinical diagnosis in those patients being evaluated for Lyme disease. The clinical findings and exposure history of the patient should drive the laboratory tests that are ordered.

1. Infectious Diseases Society of America. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis. Clinical Infectious Diseases 2006;43:1089-1134 

Figure. The Two-tier Testing Decision Tree