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. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to the joints, heart, and nervous system. Lyme disease is diagnosed based on symptoms, physical findings (e.g., rash), and the possibility of exposure to infected ticks. Laboratory testing can be helpful if used correctly and performed using validated methods.

Serologic testing is the principal means of laboratory diagnosis of Lyme disease. The Centers for Disease Control and Prevention (CDC) recommends a two-step testing process using a sensitive enzyme immunoassay (EIA) followed by a second EIA or western immunoblot assay when initial results are positive or equivocal. In contrast to these tests, which only indirectly assess prior or present exposure to B. burgdorferi, Polymerase Chain Reaction (PCR) directly tests for the presence of the spirochete in cerebrospinal fluid. CSF may be positive by PCR during the first two weeks of infection, but thereafter the detection rate is low. PCR is not recommended for urine or blood specimens.

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 penicillin.

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.

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. 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.



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. Evidence Positioning System. (10:2018). Intravenous antibiotic therapy and associated diagnostic testing for lyme disease (5.01.08). Retrieved October 2, 2019 from (27 articles and/or guidelines reviewed)

Centers for Disease Control and Prevention. (2018, December). Lyme disease: Treatment. Retrieved October 2, 2019 from

Centers for Disease Control and Prevention. (2018, December). Lyme disease: Laboratory tests that are not recommended. Retrieved October 3, 2019 from   

Centers for Disease Control and Prevention. (2019, August). Lyme disease: Diagnosis and testing. Retrieved October 3, 2019 from

Centers for Disease Control and Prevention. (2019, August). Lyme disease: Post-treatment Lyme disease syndrome. Retrieved October 3, 2019 from

International Lyme and Associated Diseases Society. (2014). Evidence assessments and guideline recommendations in lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Retrieved October 2, 2019 from

Mead, P., Petersen, J., & Hinckley, A. (2019). Updated CDC recommendation for serologic diagnosis of Lyme disease. Morbidity and Mortality Weekly Report (MMWR), 68 (32), 703. Retrieved October 3, 2019 from  

National Institute of Health. National Institute of Allergy and Infectious Diseases. (2018, November). Lyme disease diagnostics research. Retrieved October 4, 2019 from

National Institute of Health. National Institute of Allergy and Infectious Diseases. (2018, November). Lyme disease antibiotic treatment research. Retrieved November 9, 2019 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), e0168613. (Level 1 evidence)

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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