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Lyme Disease Serology

Lyme disease is caused by the spirochetes Borrelia burgdorferi and Borrelia garinii. It is the most common tick-borne infection in the United States and in Europe. In the U.S., Lyme disease is endemic in the Northeastern, mid-Atlantic and Upper Midwestern states. The blacklegged deer tick, Ixodes scapularis, is the vector of Lyme disease in the eastern and upper midwestern United States. The western blacklegged tick, I. pacificus, is the vector of Lyme disease on the Pacific Coast. Peak incidence for the onset of illness occurs in July.

Lyme disease has been a nationally notifiable condition in the United States since 1991. More than 30,000 Lyme disease cases are confirmed each year in the U.S., but the Centers for Disease Control and Prevention (CDC) estimates that approximately 300,000 cases of presumed Lyme disease go unreported each year.

A B. burgdorferi carrying tick has to be attached for at least 36 hours in order for the bacteria to be efficiently transmitted to an individual. Following transmission, the incubation period is typically 7 to 14 days, but can range from 3 to 32 days. The first phase of infection is the appearance of an erythema migrans rash, which occurs in approximately 90% of individuals. Some patients may also experience fatigue, malaise, myalgia, headache, and lymphadenopathy. During the next few weeks, untreated individuals may develop neurologic disease including facial nerve palsy, lymphocytic meningitis, and motor or sensory radiculoneuropathy. Other extracutaneous manifestations include oligoarticular arthritis involving the large joints and myocarditis with atrioventricular heart block. Patients who are treated early with appropriate antibiotics usually experience full recovery.

Since 2008, a confirmed case of Lyme disease is defined as either 1) erythema migrans in a person who had possible exposure to tick habitat in an area where Lyme disease is endemic or who had laboratory evidence of infection or 2) at least one other defined clinical manifestation of Lyme disease in a person and laboratory evidence of infection. A probable case of Lyme disease is defined as laboratory evidence of infection in a person who had Lyme disease diagnosed by a clinician but with accompanying clinical information that does not meet the clinical criteria for a confirmed case.

Because the signs and symptoms of Lyme disease may be nonspecific, serologic tests are helpful in confirming the diagnosis. The Centers for Disease Control and Prevention (CDC) recommends a 2-step approach for the serologic diagnosis of Lyme disease. The first tier consists of an enzyme immunoassay (EIA) for IgG and IgM antibodies to Borrelia burdorferi. Several screening EIA are available that differ in their antigenic composition. Some use a whole cell Borrelia burgdorferi sonicate while others use a recombinant C6 peptide for antibody detection. These enzyme immunoassays are capable of detecting antibodies to all members of the Borrelia burgdorferi complex.

Sensitivity of any of the screening EIAs is only 70 to 75% in patients with early Lyme disease, but increases to approximately 90% during later stages of disease. For this reason, patients with erythema migrans should not be tested.

A negative result does not exclude Lyme disease, especially if the sample was collected within 2 weeks of symptom onset. If Lyme disease is strongly suspected, a second specimen should be tested 4 to 6 weeks after the first. Early administration of antibiotics may weaken or delay the antibody response.

Specimens that test negative on initial screening do not need further testing. Specimens testing positive by either method should be evaluated further by a standardized Western blot immunoassay. Western blots used in the U.S. contain 3 antigens on the IgM and 10 antigens on the IgG blot. CDC requires reactivity with at least 2 IgM bands and 5 IgG bands for a Western blot to be considered positive.

Sensitivity of Lyme Western blot is also dependent on the stage of the disease when tested. Sensitivity is only 20% -50% during early disease and consists of IgM antibodies. Sensitivity increases to 80% to 100% during later stages and switches to an IgG antibody prevalence. A positive IgM Western blot generally indicates recent infection, but in some patients IgM-class antibodies persist for months to years following infection. IgG antibodies can persist for years. In patients tested within 4 weeks of symptom onset, results of both IgM and IgG Western blot should be used in the interpretation.

Specificity of the 2-tiered testing algorithm, regardless of what screening EIA is used, is high, over 99% in both healthy individuals and those with other infectious or inflammatory diseases.

The use of serologic tests for Lyme disease for screening patients with a low probability of having Lyme disease results in a large number of false-positive results. Even with highly accurate Lyme tests, ordering of Lyme disease testing for individuals who live in nonendemic areas or who have only nonspecific symptoms, such as pain or fatigue, will result in the vast majority of positive results being falsely positive, because the predictive value of a positive result is low in this setting.

Borrelia miyamotoi, a member of the relapsing fever group of Borrelia, was first reported to cause human disease in the United States in 2013. It is transmitted by the same tick species that transmit Lyme disease. Patients infected with B miyamotoi may be misdiagnosed as having Lyme disease because this infection may cause positive results with EIA used to diagnose Lyme disease.

Recently, proposals have been made to change the recommended 2-tier algorithm for serologic testing for Lyme disease from the current standard of an EIA followed by a Western blot to one in which the Western blot is replaced by an EIA that is different than the first tier EIA. For example, a first tier EIA based on a whole cell sonicate would be followed by an EIA based on recombinant C6 peptide. This approach would make testing easier, quicker and less expensive to perform. Studies using this algorithm have reported a specificity of >95%, which is equivalent to the standard algorithm using Western blot.

Specimen requirement is one SST tube of blood.

References

Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifestations of Lyme disease. Ann Intern Med 1983;99:76–82.

Lantos PM, Branda JA, Boggan JC, et al. Poor positive predictive value of Lyme disease serologic testing in an area of low disease incidence. Clin Infect Dis 2015;61:1374–80.

Hinckley AF, Connally NP, Meek JI, et al. Lyme disease testing by large commercial laboratories in the United States. Clin Infect Dis 2014;59:676–81.

Council of State and Territorial Epidemiologists. Revised national surveillance case definition for Lyme disease; 2007. http://c.ymcdn.com/sites/www.cste.org/resource/resmgr/PS/07-ID-11.pdf

Centers for Disease Control and Prevention. Two-step laboratory testing process. http://www.cdc.gov/lyme/diagnosistesting/labtest/twostep/index.html

Schwartz AM. et al. Surveillance for Lyme Disease — United States, 2008–2015. Morbidity and Mortality Weekly Report, Nov 10, 2017;66(22):1-12.

Moore A, et al. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis. 2016;22 (7):169-1177.

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