Lyme Disease AHS – G2143

Description of Procedure or Service

1. Definitions
   Lyme disease is a common multisystem inflammatory disease caused by spirochetes of the family Borreliaceae transmitted through the bite of infected tick of the genus Ixodes (Barbour, 2018). Lyme Disease affects the skin in its early, localized stage, and spreads to the joints, nervous system and other organ systems in its later, disseminated stages (Hu, 2018).
2. Background
   Lyme disease can be caused by several species in the spirochete family Borreliaceae, however infection in North America is predominately caused by B. burgdorferi. Much less commonly, in the upper mid-West, cases have been associated with B. mayonii (Beard, 2018; Pritt et al., 2016). Their taxonomy is undergoing revision, and the genus name may be represented as either Borrelia or Borreliella (Adeolu & Gupta, 2014; Margos et al., 2017).
   
   Borrelia burgdorferi occurs naturally in reservoir hosts, including small mammals and birds (Hyde, 2017). Ixodes scapularis and I. pacificus become infected with B. burgdorferi while feeding on the blood of natural reservoir hosts. Incidental transmission to humans results from the bite of an infected tick (Bacon, Kugeler, & Mead, 2008). Spirochete transmission times and virulence depend upon the tick and Borrelia species, and infection can never be excluded after a tick bite irrespective of the estimated duration of attachment time (Cook, 2015).
   
   In the earliest stage of Lyme disease B. burgdorferi disseminates from the site of the tick bite resulting in the colonization of dermal tissue and localized infection characterized by a painless bulls-eye rash, called an erythema migrans, experienced by approximately 70– 80% of patients at the site of the tick bite. This is accompanied by non-specific flu-like symptoms including headache, neck stiffness, malaise, fatigue, myalgia, and fever. During localized infection, the number of B. burgdorferi cells increases in the dermal tissue. If left untreated, B. burgdorferi can disseminate from the site of the tick bite through the bloodstream and/or lymphatic system to invade and colonize various tissues days to weeks after infection. This can affect the heart, joints, and the nervous system (Hyde, 2017).
   
   In 2016, 26,203 cases of confirmed Lyme disease were reported, and an additional 10,226 probable cases (CDC, 2017b). However some studies suggest that closer to 300,000 people are diagnosed with Lyme disease each year in the United States. Lyme disease cases are concentrated in the Northeast and upper Midwest, with 14 states accounting for over 96% of cases (Mead, 2015).
   
   Months to years after exposure to B. burgdorferi and patients can experience different manifestations including neuroborreliosis, Lyme carditis, and/or arthritis (Hyde, 2017).
   
   Even following antibiotic treatment, a subset of patients continues to present with arthritic symptoms that has been designated postinfectious, antibiotic-refractory Lyme arthritis(Hyde, 2017). The term "post-Lyme disease syndrome" is often used to describe the nonspecific symptoms (such as headache, fatigue, and arthralgias) that may persist for months after treatment of Lyme disease. For the majority of patients, these symptoms improve gradually over six months to one year (Hu, 2018).
   
   Weitzner et al (2015) found that “PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi.”
   
   Wormser et al. (2013) state that, there is no well-accepted definition of post–Lyme disease syndrome. This has contributed to confusion and controversy and to a lack of firm data on its incidence, prevalence, and pathogenesis.
   
   The diagnosis of Lyme disease is based on an individual's history of possible exposure to ticks, the presence of characteristic signs and symptoms, and the results of blood tests(Hu, 2018). Direct detection of Borrelia burgdorferi has limited application(Marques, 2015), and thus most laboratory confirmation of Lyme disease involves detection of the antibody responses against B. burgdorferi in serum (Schriefer, 2015). Serology testing is not recommended for patients who do not have symptoms typical of Lyme disease (Marques, 2015), as current assays do not distinguish between active and past infection, thus a positive result is more likely to be a false positive.
   
   The best indicator of early infection, erythema migrans, is presented in the majority of US cases and should prompt treatment without testing (Schriefer, 2015) as the lesion appears prior to development of a diagnostic, adaptive immune response (Hu, 2018).
   
   Serological testing using the two tier algorithm, comprising a first screening enzymatic immunoassay (EIA), followed by a confirmatory Western blot test, was developed to optimise specificity and sensitivity(Bunikis & Barbour, 2002). STTT is the recommended diagnostic technique for LD in clinical practice (CDC, 2017a). Although standardized 2- tier testing (STTT) detection of early, localized infection is poor, that of late disease is very good (Schriefer, 2015). Evidence of seronegative late Lyme disease is unconvincing (Halperin, 2015).
   
   Wormser (2013) developed a C6 ELISA as a single step serodiagnostic test which using a reference standard of two-tier testing, provided increased sensitivity in early Lyme disease with comparable sensitivity in later manifestations of Lyme disease. However, testing with the additional VlsE C6 antigen Western blot is not widely available at this time (Hu, 2018).
   
   Tokarz et al (2018) recently reported the development of the first multiplex, array-based assay for serodiagnosis of tick-borne diseases called the TBD-Serochip. They report that “The TBD-Serochip was designed to discriminate antibody responses to 8 major tickborne pathogens present in the United States, including Anaplasma phagocytophilum, Babesia microti, Borrelia burgdorferi, Borrelia miyamotoi, Ehrlichia chaffeensis, Rickettsia rickettsii, Heartland virus and Powassan virus. To test the performance of the TBD-Serochip, we examined sera from patients with confirmed Lyme disease, babesiosis, anaplasmosis, and Powassan virus disease. We identified a wide range of specific discriminatory epitopes that facilitated accurate diagnosis of each disease. We also identified previously undiagnosed infections. Our results indicate that the TBD-Serochip is a promising tool for a differential diagnosis not available with currently employed serologic assays for TBDs.”
3. Applicable Federal Regulations
   FDA has cleared 70 serologic assays to aid in the diagnosis of Lyme disease. Recommendations for the use and interpretation of serologic tests have been published previously (CDC, 2016). Initial testing should use an enzyme immunoassay (EIA) or immunofluorescent assay (IFA); specimens yielding positive or equivocal results should be tested further by using a standardized Western immunoblot assay. Specimens negative by a sensitive EIA or IFA do not need further testing.

***Note: This Medical Policy is complex and technical. For questions concerning the te

Policy

BCBSNC will provide coverage for Lyme disease testing when it is determined to be medically necessary because the medical criteria and guidelines noted below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. 

When Lyme disease testing is covered

Serologic testing (2-tier testing strategy) for all patients with a history of travel to a Lyme region (with or without a history of a tick bite) with compatible symptoms of Lyme disease is considered medically necessary.

When Lyme disease testing is not covered

Serologic testing is considered not medically necessary in the following situations:

1. In patients with an erythema migrans (EM) rash. Patients with skin rashes consistent with EM who reside in or have recently traveled to an endemic area should be treated for Lyme disease.
2. For screening of asymptomatic patients living in endemic areas.
3. For patients with non-specific symptoms only (eg, fatigue, myalgias/arthralgias). The use of serologic testing in populations with a low pre-test probability of Lyme disease results in a greater likelihood of false positive test results than true positive test results.

PCR-based direct detection of Borrelia burgdorferi is considered not medically necessary in the following situations

1. In patients with a short duration of neurological symptoms (<14 days) during the window between exposure and production of detectable antibodies, via CSF sample
2. In patients with Lyme carditis, as evidenced by positive serologic findings (positive or indeterminate enzyme-linked immunosorbent assay [ELISA], or positive immunoblot by CDC criteria), and associated with a high degree of artrioventricular block, or a PR interval of greater than 0.3 seconds, via blood sample
3. In patients with well documented Lyme arthritis who have such severe arthritis that it requires rapid IV antibiotic response, via synovial tissue/fluid sample

Repeat PCR-based direct detection of Borrelia burgdorferi is considered investigational in the following situations

1. As a justification for continuation of IV antibiotics beyond one month in patients with persistent symptoms
2. As a technique to follow a therapeutic response
3. Via urine sample

Other testing for Borrelia burgdorferi is considered investigational, including but not limited to

1. Genotyping and phenotyping
2. Determination of levels of the B lymphocyte chemoattractant CXCL13

Testing of the individual tick is considered not medically necessary for the diagnosis of Lyme disease

Policy Guidelines

Guidelines and Recommendations

The Centers for Disease Control (CDC, 2017a) currently 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.

• The first step uses a testing procedure called “EIA” (enzyme immunoassay) or rarely, an “IFA” (indirect immunofluorescence assay).
• If this first step is negative, no further testing of the specimen is recommended.
• If the first step is positive or indeterminate (sometimes called "equivocal"), 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 EIA/IFA and the immunoblot are both positive.

The CDC recommends serologic testing (2-tier testing strategy) for all patients with a history of travel to a Lyme region (with or without a history of a tick bite) with compatible symptoms of Lyme disease. The two steps of Lyme disease testing are designed to be done together. The CDC does not recommend skipping the first test and just doing the Western blot. Doing so will increase the frequency of false positive results and may lead to misdiagnosis and improper treatment.

Lab Tests that are not recommended (CDC, 2016)

Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. Examples of unvalidated tests include:

1. Capture assays for antigens in urine
2. Culture, immunofluorescence staining, or cell sorting of cell wall-deficient or cystic forms of B. burgdorferi
3. Lymphocyte transformation tests
4. Quantitative CD57 lymphocyte assays
5. “Reverse Western blots”
6. In-house criteria for interpretation of immunoblots
7. Measurements of antibodies in joint fluid (synovial fluid)
8. IgM or IgG tests without a previous ELISA/EIA/IFA

The Infectious Diseases Society of America (Wormser et al., 2006), The American Academy of Neurology(Halperin et al., 2007) and more recently the International Lyme and Associated Diseases Society (Cameron, Johnson, & Maloney, 2014) have published guidelines on the assessment and treatment of Lyme disease, no method of testing has been recommended over STTT.

The Infectious Diseases Society of America also recommended that

• “For prevention of Lyme disease after a recognized tick bite, routine use of antimicrobial prophylaxis or serologic testing is not recommended.”
• “Testing of ticks for tickborne infectious agents is not recommended, except in research studies”

The American College of Rheumatology (ACR, 2013) also recommends that “The musculoskeletal manifestations of Lyme disease include brief attacks of arthralgia or intermittent or persistent episodes of arthritis in one or a few large joints at a time, especially the knee. Lyme testing in the absence of these features increases the likelihood of false positive results and may lead to unnecessary follow-up and therapy. Diffuse arthralgias, myalgias or fibromyalgia alone are not criteria for musculoskeletal Lyme disease.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

ACR. (2013). ACRheum - Testing for Lyme disease | Choosing Wisely. http://www.choosingwisely.org/clinician-lists/american-college-rheumatology-testing-for-lymedisease/

Adeolu, M., & Gupta, R. S. (2014). A phylogenomic and molecular marker based proposal for the division of the genus Borrelia into two genera: the emended genus Borrelia containing only the members of the relapsing fever Borrelia, and the genus Borreliella gen. nov. containing the members of the Lyme disease Borrelia (Borrelia burgdorferi sensu lato complex). Antonie Van Leeuwenhoek, 105(6), 1049-1072. doi:10.1007/s10482-014-0164-x

Bacon, R. M., Kugeler, K. J., & Mead, P. S. (2008). Surveillance for Lyme disease--United States, 1992-2006. MMWR Surveill Summ, 57(10), 1-9.

Barbour, A. (2018). Microbiology of Lyme disease - UpToDate. In J. Mitty (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/microbiology-of-lymedisease?source=see_link.

Beard, C. B. (2018). Epidemiology of Lyme disease - UpToDate. In J. Mitty (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/epidemiology-of-lymedisease?source=see_link.

Bunikis, J., & Barbour, A. G. (2002). Laboratory testing for suspected Lyme disease. Med Clin North Am, 86(2), 311-340.

Cameron, D. J., Johnson, L. B., & Maloney, E. L. (2014). Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther, 12(9), 1103-1135. doi:10.1586/14787210.2014.940900

CDC. (2017a, 2017-08-07T05:14:10Z). Diagnosis and Testing | Lyme Disease | CDC. Retrieved from https://www.cdc.gov/lyme/diagnosistesting/index.html

CDC. (2017b). Lyme disease data tables | Lyme Disease | CDC. Retrieved from https://www.cdc.gov/lyme/stats/tables.html.

Cook, M. J. (2015). Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med, 8, 1-8. doi:10.2147/ijgm.s73791

Halperin, J. J. (2015). Chronic Lyme disease: misconceptions and challenges for patient management. Infect Drug Resist, 8, 119-128. doi:10.2147/idr.s66739

Halperin, J. J., Shapiro, E. D., Logigian, E., Belman, A. L., Dotevall, L., Wormser, G. P., . . . Bever, C. T., Jr. (2007). Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 69(1), 91-102. doi:10.1212/01.wnl.0000265517.66976.28

Hu, L. (2018). Diagnosis of Lyme disease - UpToDate. In J. Mitty (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/diagnosis-of-lymedisease?search=lyme%20disease&source=search_result&selectedTitle=3~150&usage_type=defaul t&display_rank=3.

Hyde, J. A. (2017). Borrelia burgdorferi Keeps Moving and Carries on: A Review of Borrelial Dissemination and Invasion. Front Immunol, 8. doi:10.3389/fimmu.2017.00114

Margos, G., Marosevic, D., Cutler, S., Derdakova, M., Diuk-Wasser, M., Emler, S., . . . Fingerle, V. (2017). There is inadequate evidence to support the division of the genus Borrelia. Int J Syst Evol Microbiol, 67(4), 1081-1084. doi:10.1099/ijsem.0.001717

Marques, A. R. (2015). Laboratory diagnosis of Lyme disease: advances and challenges. Infect Dis Clin North Am, 29(2), 295-307. doi:10.1016/j.idc.2015.02.005

Mead, P. S. (2015). Epidemiology of Lyme disease. Infect Dis Clin North Am, 29(2), 187-210. doi:10.1016/j.idc.2015.02.010

Pritt, B. S., Mead, P. S., Johnson, D. K. H., Neitzel, D. F., Respicio-Kingry, L. B., Davis, J. P., . . . Petersen, J. M. (2016). Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis, 16(5), 556- 564. doi:10.1016/s1473-3099(15)00464-8

Schriefer, M. E. (2015). Lyme Disease Diagnosis: Serology. Clin Lab Med, 35(4), 797-814. doi:10.1016/j.cll.2015.08.001

Tokarz, R., Mishra, N., Tagliafierro, T., Sameroff, S., Caciula, A., Chauhan, L., . . . Lipkin, W. I. (2018). A multiplex serologic platform for diagnosis of tick-borne diseases. Sci Rep, 8. doi:10.1038/s41598-018-21349-2

Weitzner, E., McKenna, D., Nowakowski, J., Scavarda, C., Dornbush, R., Bittker, S., . . . Wormser, G. P. (2015). Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease. Clin Infect Dis, 61(12), 1800-1806. doi:10.1093/cid/civ735

Wormser, G. P., Dattwyler, R. J., Shapiro, E. D., Halperin, J. J., Steere, A. C., Klempner, M. S., . . . Nadelman, R. B. (2006). The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis, 43(9), 1089-1134. doi:10.1086/508667

Wormser, G. P., Schriefer, M., Aguero-Rosenfeld, M. E., Levin, A., Steere, A. C., Nadelman, R. B., . . . Dumler, J. S. (2013). Single-tier testing with the C6 peptide ELISA kit compared with twotier testing for Lyme disease. Diagn Microbiol Infect Dis, 75(1), 9-15. doi:10.1016/j.diagmicrobio.2012.09.003

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will provide coverage for Lyme disease testing when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (sk)