Testing and Treatment for Lyme Disease
DESCRIPTION
Lyme disease is a multisystem inflammatory disease caused by the spirochete Borrelia (B.) burgdorferi and transmitted by the bite of an infected ixodid tick endemic to Northeastern, North Central, and Pacific coastal regions of the U.S. The disease is characterized by stages, beginning with localized infection of the skin (erythema migrans), followed by dissemination to many sites. Manifestations of early disseminated disease may include lymphocytic meningitis, facial palsy, painful radiculoneuritis, atrioventricular nodal block, or migratory musculoskeletal pain. Months to years later, the disease may be manifested by intermittent oligoarthritis, particularly involving the knee joint, chronic encephalopathy, spinal pain, or distal paresthesias. 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 are 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.
Currently, the Centers for Disease Control and Prevention (CDC) recommend a two-step method for the serologic diagnosis of Lyme disease:
Enzyme-Linked Immunosorbent Assay (ELISA) for Borrelia burgdorferi Antibodies
This test is a screening serologic test for Lyme disease. ELISA tests are available to detect IgM or IgG antibodies or to detect both antibody types together. More recently developed tests using recombinant or synthetic antigens have improved diagnostic sensitivity. For example, the FDA-approved C6 ELISA is highly sensitive to infection, and is under study as an indicator of antibiotic therapy efficacy. A positive or indeterminate ELISA test result alone is inadequate serologic evidence of Lyme disease. All of these tests must be confirmed with an immunoblot test. In addition, results must be correlated with the clinical picture.
(Western) Immunoblot
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. Typically, several clinically significant antigens are tested. According to CDC criteria, the test result is considered positive if 2 of the 3 most common IgM antibody bands to spirochetal antigens are present, or 5 of the 10 most frequent IgG antibody bands are present. Because the CDC criteria were developed for surveillance, they are conservative and may miss true Lyme disease cases. Some support the use of more liberal criteria for a positive result in clinical diagnosis; however, alternative criteria have not been well validated. Criteria for interpreting immunoblot results are different in Europe than in the United States due to differences in prevalent Borrelia species causing disease.
Other tests include:
Polymerase Chain Reaction (PCR): In contrast to the above 2 serologic tests, which only indirectly assess prior or present exposure to B. burgdorferi, PCR directly tests for the presence of the spirochete. Because PCR technology involves amplification of DNA from a portion of B. burgdorferi, there is a high risk of exogenous contamination, resulting in false-positive results. Positive results in the absence of clear clinical indicators or positive serology are not definitive for diagnosis. In addition, the test cannot distinguish between live spirochetes or fragments of dead ones. The PCR technique has been studied using a variety of specimens. PCR has the best detection rates for skin biopsies from individuals with erythema migrans and for synovial tissue (and synovial fluid, to a lesser extent) from individuals with Lyme arthritis. 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.
Evaluation of Cerebrospinal Fluid (CSF): Aside from the standard evaluation of CSF for pleocytosis, protein levels, and glucose levels, various tests are available to determine whether anti-B. burgdorferi antibodies are being selectively produced within the central nervous system. Techniques include a variety of immunoassays. For example, intrathecal antibody production can be detected by the CSF/serum index of B. burgdorferi antibodies. CSF and serum samples diluted to match the total IgG concentration in CSF are run in parallel in an IgG ELISA. Excess Borrelia-specific antibody in CSF indicates a positive result. As noted, PCR can also be used to detect the spirochete in the CSF, most successfully within the first 2 weeks of infection.
Borrelia PCR also provides information on which of the 3 major species pathogenic for humans has been found in the specimen tested (genotyping).
T-lymphocyte proliferation assays are not recommended as diagnostic tests; they are difficult to perform and standardize, and their sensitivity is not well characterized (phenotyping).
Evaluation of the Chemoattractant CXCL13: CXCL13 is a B lymphocyte chemoattractant and has been reported to be elevated in acute neuroborreliosis, and a potential marker for successful treatment.
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 chronic infection of B. burgdorferi (i.e. chronic Lyme Disease, post-treatment Lyme disease, or late Lyme disease).
POLICY
Testing by the following methods to determine lyme infection is considered medically necessary:
Serologic findings by Enzyme-Linked Immunosorbent Assay (ELISA) for B. burgdorferi antibodies or (western) immunoblot
Polymerase Chain Reaction (PCR) based direct detection in cerebral spinal fluid (CSF), synovial tissue, or synovial fluid
Treatment for the following conditions is considered medically necessary:
Lyme disease
Neuroborreliosis
Lyme carditis
Lyme arthritis
Repeat or prolonged courses of antibiotic therapy greater than 4 weeks are considered not medically necessary.
Other testing, including, but not limited to the following is considered investigational:
Repeat PCR-based direct detection of B. burgdorferi
As a justification for continuation of intravenous antibiotics beyond 1 month in individuals with persistent symptoms
As a technique to follow therapeutic response
PCR-based direct detection of B. burgdorferi in urine samples
Genotyping or phenotyping of B. burgdorferi
Determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment
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ADDITIONAL INFORMATION
No evidence was found to support the safety or efficacy of repeated or prolonged antibiotic treatment (greater than 4 weeks). Neither fibromyalgia nor chronic fatigue syndrome have been shown to be responsive to antibiotic therapy.
Additionally, the Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) documents the following recommendations:
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. In an attempt to provide a framework for future research on this subject and to reduce diagnostic ambiguity in study populations, a definition for post-Lyme disease is proposed. Whatever definition is eventually adopted, having once had objective evidence of B. burgdorferi infection must be a condition sine qua non. Furthermore, when laboratory testing is done to support the original diagnosis of Lyme disease, it is essential that it be performed by well-qualified and reputable laboratories that use recommended and appropriately validated testing methods and interpretive criteria. Test methods (such as urine antigen tests or blood microscopy for detection of Borrelia species) that have not been validated should not be used.
To date, there is no convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection among individuals after receipt of recommended treatment regimens for Lyme disease. Antibiotic therapy has not proven to be useful and is not recommended for individuals with chronic (./= 6 months) subjective symptoms after administration of recommended treatment regimes for Lyme disease.
No data were found in the published literature to show that repetition of PCR-based direct detection of B. burgdorferi, 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.
SOURCES
American Academy of Neurology. (2007, July). Practice parameter: Treatment of nervous system lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Retrieved September 10, 2010 from http://www.neurology.org/cgi/rapidpdf/01.wnl.0000265517.66976.28v1.pdf.
Auwaeter, P. G. (2007). Point: Antibiotic therapy is not the answer for patients with persisting symptoms attributable to lyme disease. Clinical Infectious Diseases, 45 (2), 143-148.
BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2010). Intravenous antibiotic therapy and associated diagnostic testing for lyme disease (5.01.08). Retrieved February 11, 2011 from BlueWeb. (20 articles and/or guidelines reviewed)
Bratton, R. L., Whiteside, J. W., Hovan, M. J., Engle, R. L., & Edwards, F. D. (2008). Diagnosis and treatment of lyme disease. Mayo Clinic Proceedings, 83 (5), 566-571.
Centers for Disease Control and Prevention. (2009, September). Lyme disease treatment and prognosis. Retrieved September 10, 2010 from http://www.cdc.gov/ncidod/dvbid/lyme/ld_humandisease_treatment.htm.
Feder, Jr., H. M., Johnson, B. J. B., O’Connell, S., Shapiro, E. D., Steere, A. C., Wormser, G. P., et al. (2007). A critical appraisal of “chronic lyme disease”. The New England Journal of Medicine, 357 (14), 1422-1430.
Klempner, M. S., Hu, L. T., Evans, J., Schmid, C. H., Johnson, G. M., Trevino, R. P., et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of lyme disease. The New England Journal of Medicine, 345 (2), 85-92. (Level 1 Evidence - Industry sponsored)
Marques. A. (2008). Chronic lyme disease: A review. Infectious Disease clinics of North America, 22 (2), 341-360.
Winifred S. Hayes, Inc. Medical Technology Directory. (2010, August). Intravenous antibiotic treatment for late-stage lyme disease. Retrieved September 10, 2010 from www.Hayesinc.com/subscribers. (42 articles and/or guidelines reviewed)
Winifred S. Hayes, Inc. Medical Technology Directory. (2010, December). Long-term antibiotic therapy for chronic lyme disease. Retrieved January 20, 2011 from www.Hayesinc.com/subscribers. (48 articles and/or guidelines reviewed)
Womerer, G. P., Dattwyler, R. J., Shapiro, D., Halperin, J. J., Steere, A. C., Klempner, M. S., et al (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. Clinical Infectious Diseases, 42 (9), 1089-1134.
ORIGINAL EFFECTIVE DATE: 5/9/2009
MOST RECENT REVIEW DATE: 10/8/2011
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