BlueCross BlueShield of Tennessee Medical Policy Manual

Testing and Treatment for Lyme Disease

Does not apply to BlueCare, please refer to the BlueCare policy.


Lyme disease is a multisystem inflammatory disease caused by the spirochete Borrelia (B.) burgdorferi and transmitted by the bite of an infected tick. The disease is characterized by stages, beginning with localized infection of the skin, followed by dissemination to many sites. Diagnostic testing for Lyme disease is challenging and can lead to overdiagnosis and overtreatment. While most manifestations of Lyme disease can be adequately treated with oral antibiotics, intravenous antibiotics are indicated in some individuals with neurologic involvement or atrioventricular heart block. Typical intravenous therapy consists of a 2- to 4-week course of ceftriaxone or cefotaxime, both third-generation cephalosporins, or penicillin or chloramphenicol.

Over-diagnosis and over-treatment of Lyme disease is common due to its nonspecific symptoms, a lack of standardization of serologic tests, and difficulties in interpreting serologic test results. In particular, individuals with chronic fatigue syndrome or fibromyalgia are commonly misdiagnosed as possibly having Lyme disease and undergo inappropriate IV antibiotic therapy.

The Centers for Disease Control and Prevention (CDC) recommends a two-step process when testing blood for evidence of antibodies against the Lyme disease bacteria. Both steps can be done using the same blood sample:

  1. Enzyme-Linked Immunosorbent Assay (ELISA) for Borrelia burgdorferi Antibodies

This is the first step in a two-step process. If this first step is negative, no further testing of the specimen is recommended. If the first step is positive or indeterminate, the second step should be performed. The second step uses a test called an immunoblot test, commonly, a “Western blot” test. Results are considered positive only if the ELISA and the immunoblot are both positive. A positive or indeterminate ELISA test result alone is inadequate serologic evidence of Lyme disease. In addition, results must be correlated with the clinical picture.

  1. Immunoblot (Western blot)

This test is used to confirm the serologic diagnosis of Lyme disease in individuals with positive or indeterminate ELISA tests. In contrast to the standard ELISA test, the immunoblot investigates the specific antibody response to the different antigens of B. burgdorferi. Criteria for interpreting immunoblot results are different in Europe than in the UnitedStates due to differences in prevalent Borrelia species.

Other tests include:

The CDC further recommends not using the following tests:

The terms post-Lyme disease, late Lyme disease, post-treatment chronic Lyme disease, and chronic Lyme disease are intended to describe individuals who have had well-documented Lyme disease, have been treated with antibiotic therapy, and who have continued to be symptomatic. Following antibiotic treatment, some symptoms may persist, such as in Lyme arthritis. These symptoms may be related to various self-sustaining inflammatory mechanisms rather than persistent infection. Based on the available literature, the preferred terminology is late Lyme disease. However, there is no credible evidence to support the existence of continued or chronic infection of the spirochete B. burgdorferi organism itself.

This medical policy does not apply to BlueCare. Please refer to the BlueCare policy.



This medical policy does not apply to BlueCare. Please refer to the BlueCare policy.


No evidence was found to support the safety or efficacy of repeated or prolonged antibiotic treatment (greater than 4 weeks). Fibromyalgia and chronic fatigue syndrome are the diseases most commonly confused with Lyme disease and neither has been shown to be responsive to antibiotic therapy.

No data were found in the published literature to show that repetition of PCR-based direct detection of B. burgdorferi in urine samples, evaluation of the genotype or phenotype of B. burgdorferi, or the B lymphocyte chemoattractant CXCL13 are effective in improving diagnosis, individual management, or outcomes.


BlueCross BlueShield Association. Medical Policy Reference Manual. (10:2016). Intravenous antibiotic therapy and associated diagnostic testing for lyme disease (5.01.08). Retrieved November 9, 2016 from BlueWeb. (31 articles and/or guidelines reviewed)

Centers for Disease Control and Prevention. (2015, March). Post-treatment lyme disease syndrome. Retrieved November 9, 2016 from

Centers for Disease Control and Prevention. (2015, March). Two-step laboratory testing process. Retrieved November 9, 2016 from

Centers for Disease Control and Prevention. (2015, November). Laboratory tests that are not recommended. Retrieved December 31, 2015 from 

Eriksson, P., Schroder, M., Nevanlinna, A., Panelius, J., & Ranke, A. (2013). The many faces of solitary and multiple erythema migrans. Acta Dermato-Venerelogica, 2013 (93), 1-8. (Level 4 evidence)

European Federation of Neurological Sciences. (2010). EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. European Journal of Neurology, 17 (1) 8-16.

Infectious Diseases Society of America (IDSA) (2006, reaffirmed in 2010) The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Retrieved November 9, 2016 from:

National Institute of Health. National Institute of Allergy and Infectious Diseases. (2015, September) Chronic lyme disease. Retrieved November 9, 2016 from:

National Institute of Health. National Institute of Allergy and Infectious Diseases. (2016, September) Lyme disease diagnostics research. Retrieved November 9, 2016 from:

National Institute of Health. National Institute of Allergy and Infectious Diseases. (2014, December) Lyme disease antibiotic treatment research. Retrieved November 9, 2016 from:

Waddell, L., Greig, J., Mascarenhas, M., harding, S., Lindsay, R., & Ogden, N. (2016). The accuracy of diagnostic tests for lyme disease in humans, a systematic review and meta-analysis of North American research. PLos ONE, 11 (12), doi:10.1371/journal.pone.0168613. (Level 1 evidence)

Wormser, G., Shapiro, E., & Strle, F. (2017). Studies that report unexpected positive blood cultures for lyme Borrelia - are they valid? Diagnostic Microbiology and Infectious Disease, 2017 Jun 29 doi:10.1016/j.diagmicrobio.2017.07.009 [Epub ahead of print]. Abstract retrieved October 16, 2017 from PubMed database.

Yang, J., Han, X., Liu, A., Bao, F., Peng, Y., Tao, L., et al. (2017). Chemokine CXC ligand 13 in cerebrospinal fluid can be used as an early diagnostic biomarker for lyme neuroborreliosis: a meta-analysis. Journal of Interferon & Cytokine Research, 37 (10), 433-439. Abstract retrieved October 16, 2017 from PubMed database.




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