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Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease

Policy Number: MP-359

Latest Review Date: October 2021

Category:  Pharmacology                                                      

 

POLICY

Effective for dates of service on or after February 19, 2021

Treatment of Lyme disease (LD) consists of oral antibiotics, except for the following indications:

An initial 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in members with neuroborreliosis with objective neurologic complications of documented Lyme disease (see the following for methods of documentation).

Objective neurologic findings include:

  • Lymphocytic meningitis with documented cerebrospinal fluid (CSF) abnormalities
  • Encephalitis or encephalomyelitis with documented CSF abnormalities
  • Cranial neuropathy, other than uncomplicated cranial nerve palsy, with documented CSF abnormalities
  • Radiculopathy
  • Polyneuropathy

Lyme carditis is suspected based on presence of one or more of the following:

  • A high degree of artrioventicular block
  • A PR interval of greater than 0.3 seconds
  • Myopericarditis

Lyme arthritis with persistent, recurrent, or worsening joint swelling that has not resolved after a recommended course of oral antibiotic therapy.

One repeat 2- to 4- week course of IV antibiotic therapy may be considered medically necessary when all of the following criteria are met:

  • Criteria for initial course of IV antibiotic therapy are met
  • Laboratory values confirming Lyme disease have been obtained within the past 3 months
  • The patient has completed the initial course of IV antibiotic therapy
  • One or more of the following are met:
    • The initial infection has relapsed
    • Organ damge as a result of Lyme disease has progressed
    • Finding of a new focus or type of organ damage

Lyme disease may be documented either on the basis of serologic testing or by clinical findings of erythema migrans in early infection. Documentation of CSF abnormalities is required for suspected central nervous system (CNS) infection, as indicated below.

Serologic documentation of infection requires:

  • Positive or indeterminate enzyme immunoassay (EIA or ELISA) followed by either of the following:
    • Positive immunoblot blot by Centers for Disease Control and Prevention (CDC) criteria; or
    • Second positive enzyme immunoassay (EIA oe ELISA)

Documented CSF abnormalities include ALL of the following:

  • Pleocytosis;
  • Evidence of intrathecal production of Borrelia burgdorferi antibodies in CSF; and
  • Increased protein levels.

Polymerase chain reaction (PCR)-based direct detection of B. burgdorferi (by direct or amplified probe) in CSF samples may be considered medically necessary and may replace serologic documentation of infection in members with a short duration of neurologic symptoms (<14 days) during the window between exposure and production of detectable antibodies.

Documentation of Lyme carditis may include PCR-based direct detection of B. burgdorferi in the blood when results of serologic studies are equivocal.

Documentation of Lyme arthritis may include PCR-based direct detection of B. burgdorferi in the synovial tissue or fluid when results of serologic studies are equivocal.

Intravenous antibiotic therapy for Lyme disease is considered not medically necessary in the following situations:

  • Members with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence for Lyme disease;
  • Members with seronegative LD in the absence of CSF antibodies;
  • Initial therapy in patients with Lyme arthritis without coexisting neurologic symptoms;
  • Cranial nerve palsy (e.g. Bell’s palsy) without clinical evidence of meningitis;
  • Post-antibiotic Lyme arthritis (unresponsive to 2 courses of oral antibiotics or to 1 course of oral and 1 course of intravenous antibiotic therapy);
  • Members with vague systemic symptoms without supporting serologic or CSF studies;
  • Members with a positive ELISA test, unconfirmed by an immunoblot or Western blot test (see definition above);
  • Members with an isolated positive serologic test in the setting of multiple negative serologic studies;
  • Members with chronic (> 6 months) subjective symptoms (“post-Lyme syndrome”) after receiving recommended treatment regimens for documented LD.

Repeat PCR-based direct detection of B. burgdorferi (by direct or amplified probe) is considered investigational in the following situations:

  • As a justification for continuation of IV antibiotics beyond 1 month in patients with persistent symptoms
  • As a technique to follow therapeutic response

PCR-based direct detection of B. burgdorferi in urine samples is considered investigational in all clinical situations.

Genotyping or phenotyping of B. burgdorferi is considered investigational.

Determination of levels of the B lymphocyte chemoattractant CXCL 13 for diagnosis or monitoring treatment is considered investigational.

Other diagnostic testing including but not limited to “stand alone” C6 peptide ELISA is considered investigational.

__________________________________________________________________________________________________________________________

Effective for dates of service prior to February 19, 2021

Treatment of Lyme disease (LD) consists of oral antibiotics, except for the following indications:

A 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in members with neuroborreliosis with objective neurologic complications of documented LD (see the following for methods of documentation).

Objective neurologic findings include:

  • Lymphocytic meningitis with documented cerebrospinal fluid (CSF) abnormalities
  • Cranial neuropathy, other than uncomplicated cranial nerve palsy, with documented CSF abnormalities
  • Encephalitis or encephalomyelitis with documented CSF abnormalities
  • Radiculopathy
  • Polyneuropathy

Lyme disease may be documented either on the basis of serologic testing or by clinical findings of erythema migrans in early infection. Documentation of CSF abnormalities is required for suspected central nervous system (CNS) infection, as indicated above.

Serologic documentation of infection requires:

  • Positive or indeterminate enzyme-linked immunosorbent assay (ELISA), AND
  • Positive immunoblot blot by Centers for Disease Control and Prevention (CDC) criteria.

Documented CSF abnormalities include ALL of the following:

  • Pleocytosis;
  • Evidence of intrathecal production of Borrelia burgdorferi antibodies in CSF; and
  • Increased protein levels.

Polymerase chain reaction (PCR)-based direct detection of B. burgdorferi (by direct or amplified probe) in CSF samples may be considered medically necessary and may replace serologic documentation of infection in members with a short duration of neurologic symptoms (<14 days) during the window between exposure and production of detectable antibodies.

A single2- to 4-week course of IV antibiotics may be considered medically necessary in members with Lyme carditis, as evidenced by positive serologic findings (defined above) and associated with a high degree of atrioventricular block or a PR interval of greater than 0.3 second. Documentation of Lyme carditis may include PCR-based direct detection of B. burgdorferi in the blood when results of serologic studies are equivocal.

A single 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in the small subset of members with well-documented Lyme arthritis who have such severe arthritis that it requires the rapid response associated with IV antibiotics. Documentation of Lyme arthritis may include PCR-based direct detection of B. burgdorferi in the synovial tissue or fluid when results of serologic studies are equivocal.

Intravenous antibiotic therapy is considered not medically necessary in the following situations:

  • Members with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence for Lyme disease;
  • Members with seronegative LD in the absence of CSF antibodies;
  • Initial therapy in patients with Lyme arthritis without coexisting neurologic symptoms;
  • Cranial nerve palsy (e.g. Bell’s palsy) without clinical evidence of meningitis;
  • Antibiotic-refractory Lyme arthritis (unresponsive to 2 courses of oral antibiotics or to 1 course of oral and 1 course of intravenous antibiotic therapy);
  • Members with vague systemic symptoms without supporting serologic or CSF studies;
  • Members with a positive ELISA test, unconfirmed by an immunoblot or Western blot test (see definition above);
  • Members with an isolated positive serologic test in the setting of multiple negative serologic studies;
  • Members with chronic (> 6 months) subjective symptoms (“post-Lyme syndrome”) after receiving recommended treatment regimens for documented LD.

Repeat or prolonged courses (greater than 4 weeks) of intravenous antibiotic therapy is considered not medically necessary.

Repeat PCR-based direct detection of B. burgdorferi (by direct or amplified probe) is considered not medically necessary and investigational in the following situations:

  • As a justification for continuation of IV antibiotics beyond 1 month in patients with persistent symptoms
  • As a technique to follow therapeutic response

PCR-based direct detection of B. burgdorferi in urine samples is considered not medically necessary and investigational in all clinical situations.

Genotyping or phenotyping of B. burgdorferi is considered not medically necessary and investigational.

Determination of levels of the B lymphocyte chemoattractant CXCL 13 for diagnosis or monitoring treatment is considered not medically necessary and investigational.

Other diagnostic testing including but not limited to “stand alone” C6 peptide ELISA is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Lyme disease (LD) is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi and transmitted by the bite of an infected Ixodes scapularis (northeastern U.S.) or Ixodes pacificus (Pacific coast, most common in Northern California) tick. 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 (AV) 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 LD can be adequately treated with oral antibiotics, intravenous (IV) antibiotics are indicated in some patients with disseminated Lyme disease. The following paragraphs describe the various manifestations of Lyme disease, therapies, and the various laboratory tests used to support the diagnosis of LD.

Manifestations

Erythema migrans

Erythema migrans appears at the site of the tick bite and manifests generally between 7 to 14 days after the bite. The lesions typically expand slowly over the course of days or weeks, often with central clearing. If multiple lesions are present, it is considered a sign of early disseminated disease.

Neuroborreliosis

Lymphocytic meningitis, characterized by head and neck pain, may occur during the acute disseminated stage of the disease. Inpatients with meningitis, the cerebrospinal fluid (CSF) will typically show a lymphocytic pleocytosis (lymphocyte count greater thannormal) with increased levels of protein and normal glucose levels. Intrathecal production of antibodies directed at spirochetalantigens is also typically present. Other manifestations of early disseminated disease can include cranial neuritis (including unilateralor bilateral facial palsy) and peripheral nervous system manifestations. Cranial neuritis, most frequently Bell palsy, may present earlyin the course of disseminated Lyme disease, occasionally before the development of antibodies. Peripheral nervous system manifestations of Lyme disease include paresthesias or radicular pain with only minimal sensory signs. Patients typically exhibit electromyographic or nerve conduction velocity abnormalities.

Neurological manifestations of late-stage dissemination can include mononeuropathy multiplex, encephalomyelitis, and subtle encephalopathy. A subacute encephalopathy is characterized by subtle disturbances in memory, mood, sleep, or cognition accompanied by fatigue. The symptoms are nonspecific and overlap with fibromyalgia and chronic fatigue syndrome. Much rarer, but of greater concern, is the development of encephalomyelitis, characterized by spastic paraparesis, ataxias, cognitive impairment, bladder dysfunction, and cranial neuropathy.

Lyme Carditis

Lyme carditis may appear during the early dissemination stage of the disease; symptoms include atrioventricular block, tachyarrhythmias, and myopericarditis.  The most common abnormality is fluctuatuing degrees of AV block.  

Lyme Arthritis

Lyme arthritis is a late manifestation of infection and is characterized by an elevated IgG response to B. burgdorferi and intermittent attacks of oligoarticular arthritis, primarily in the large joints such as the knee. However, both large and small joints may be affected.  

Diagnostic Testing

Overview

The optimum method of testing for Lyme disease depends on the stage of the disease. Diagnostic testing may not be necessary whena diagnosis can be made clinically in patients with a recent tick bite or exposure and the presence of the characteristic rash of erythema migrans, particularly in patients presenting early before the development of a detectable serum antibody response. While diagnosis of Lyme disease is generally based on the clinical picture and demonstration of specific antibodies (see below), polymerasechain reaction (PCR)-based technology can detect the spirochete in the central nervous system in cases of neuroborreliosis, in the synovial fluid of cases of Lyme arthritis, and rarely in skin biopsy specimens of those with atypical dermatologic manifestations. However, while PCR-based tests can identify organisms in skin biopsy specimens of patients with dermatologic manifestations (i.e.,erythema migrans), this diagnosis is typically made clinically, and antibiotic therapy is started empirically.

For Lyme neuroborreliosis, CSF examination may be useful in select patients. In patients with suspected neuroborreliosis, evaluation allows for exclusion of bacterial or viral meningitis and can provide a more definitive diagnosis. However, direct detection of B.burgdorferi in CSF, by PCR or culture, is usually not possible in patients with Lyme neuroborreliosis.

Similarly, diagnosis of Lyme arthritis is based on clinical and serologic studies without the need for synovial tissue or fluid. Finally, intrathecal antibody production is considered a more sensitive test than PCR-based cerebral spinal fluid (CSF) detection in patients with suspected neuroborreliosis. Polymerase chain reaction (PCR), may be clinically useful as a second approach in patients with a short duration of neurologic symptoms (<14 days) during the window between exposure and the emergence of detectable levels of antibodies in the CSF. PCR-based detection is typically not performed in the urine due to the variable presence of endogenous polymerase inhibitors that affect test sensitivity.

Fibromyalgia and chronic fatigue syndrome are the diseases most commonly confused with Lyme disease. Fibromyalgia is characterized by musculoskeletal complaints, multiple trigger points, difficulty in sleeping, generalized fatigue, headache, or neck pain.The joint pain associated with fibromyalgia is typically diffuse, in contrast to Lyme arthritis, which is characterized by marked joint swelling in 1 or more joints at a time, with few systemic symptoms. Chronic fatigue syndrome is characterized by multiple subjective complaints, such as overwhelming fatigue, difficulty in concentration, and diffuse muscle and joint pain. In contrast with Lyme disease,both of these conditions lack joint inflammation, have normal neurologic test results, or have test results suggesting anxiety or depression. Neither fibromyalgia nor chronic fatigue syndrome has been shown to respond to antibiotic therapy.

Serologic Tests

The antibody response to infection with B. burgdorferi follows a typical pattern. During the first few weeks after the initial onset of infection, there is no antibody production. The specific IgM response characteristic of acute infection peaks between the third and sixth week. The specific IgG response develops only after months and includes antibodies to a variety of spirochetal antigens. IgG antibodies produced in response to LD may persist for months or years. Thus, detection of IgG antibodies only indicates exposure, either past or present. In LD endemic areas, underlying asymptomatic seropositivity may range from 5%–10%. Thus, as with any laboratory test, interpretation of serologic tests requires close correlation with the patients’ signs and symptoms. For example, patients with vague symptoms of LD, chronic fatigue syndrome, or fibromyalgia may undergo multiple serologic tests over many weeks to months to establish the diagnosis of LD. Inevitably, in this setting of repeat testing, one enzyme-linked immunosorbent assay (ELISA) or test, whether IgG or IgM, may be reported as weakly positive or indeterminate. These results most likely represent false positive test results in the uninfected patient who has had long-standing symptoms from a different condition and previously negative test results.

Currently, the Centers for Disease Control and Prevention recommend a 2-tiered method for the serologic diagnosis of Lymedisease. This can be accomplished using the standard 2-tiered testing process, which uses a sensitive enzyme immunoassay (EIA) or immunofluorescence assay, followed by a western immunoblot assay for specimens yielding positive or equivocal results. Additionally, a modified 2-test methodology can be used, which uses a second EIA in place of the western immunoblot assay.

Enzyme-Linked Immunosorbent Assay for Borrelia Burgdorferi Antibodies

This ELISA test is a screening serologic test for Lyme disease. ELISA tests are available to detect IgM or IgG antibodies or both antibody types together. More recently developed tests using recombinant or synthetic antigens have improved diagnostic sensitivity. For example, the U.S. Food and Drug Administration‒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 a Western blot or a second EIA. The overall predictive values is oncreased when correlated with the clinical picture.

(Western) Immunoblot

This immunoblot test is used to confirm the serologic diagnosis of Lyme disease in patients with positive or indeterminate ELISA tests. In contrast with 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 Centers for Disease Control and Prevention 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 Centers for Disease Control and Prevention 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. U.S. criteria for interpreting immunoblot results differ from those in Europe due to differences in prevalent Borrelia species causing disease.

Nonserologic Tests

Polymerase Chain Reaction (PCR)

In contrast to the previously discussed serologic tests, which indirectly assess prior or present exposure to B. burgdorferi, PCR directly tests for the presence of B. burgdorferi DNA. Because PCR technology involves the amplification of DNA from a portionof B. burgdorferi, there is a high-risk of exogenous contamination, resulting in false-positive results. Positive results in the absence ofclear clinical indicators or positive serology are not definitive for diagnosis. Also, the test cannot distinguish between live spirochetesor fragments of dead ones. The PCR technique has been studied using various specimens. PCR has the best detection rates for skinbiopsies from patients with erythema migrans (but who may not be indicated with a recent history of tick bite or exposure) and forsynovial tissue (and synovial fluid, to a lesser extent) from patients with Lyme arthritis. Cerebrospinal fluid may be positive by PCRduring the first 2 weeks of infection but after that the detection rate is low. PCR is not recommended for urine or blood specimens.However, PCR-based direct detection of B. burgdorferi in the blood may be useful for documenting Lyme carditis when results ofserologic studies are equivocal.

Borrelia PCR also provides information on which of the three major species pathogenic for humans has been found in the specimen tested (genotyping).

T-Cell Proliferative Assay

T-lymphocyte proliferation assays are not recommended as diagnostic tests because they are difficult to perform and standardize, and their sensitivity is not well characterized.

Chemoattractant CXCL13

CXCL13 is a B-lymphocyte chemoattractant that has been reported to be elevated in acute neuroborreliosis and other inflammatory disorders in the central nervous system. It is being investigated as an adjunvt in identifying infection and as a potneitla marker for successful treatment. The Centers for Disease Contril and Prevention notes that standardized interpretation criteria is required before this test can be recommended.

Treatment of Lyme Disease

Recommended treatment regimens are based on the stage and manifestations of Lyme disease.

Most patients can be treated with oral antibiotics, such as doxycycline, amoxicillin, or cefuroxime. Specific durations of therapy are dependent on the type of manifestations present. Treatment with IV antibiotics may be indicated in patients with central nervous system or peripheral neurologic involvement and in a small subset of patients with heart block or documented Lyme arthritis who have not responded to oral antibiotics. Typical IV therapy consists of a 2- to 4-week course of ceftriaxone, cefotaxime or penicillin. No data have suggested that prolonged or repeated courses of IV antibiotics are effective. Lack of effect should suggest an incorrect diagnosis or slow resolution of symptoms, which is commonly seen in Lyme disease. Also, some symptoms may persist after treatment, such as Lyme arthritis; this phenomenon may be related to various self-sustaining inflammatory mechanisms rather than persistent infection.

KEY POINTS:

The most recent literature review was performed through September 1, 2021.

Summary of Evidence

For individuals who are suspected of having Lyme disease who receive genotyping or phenotyping of B. burgdorferi subspecies, the evidence is limited. Relevant outcomes are change in disease status and morbid events. Polymerase chain reaction-based testing for B. burgdorferi genospecies is feasible. However, no evidence was identified that knowledge of the B. burgdorferi genotype or phenotype could be used to improve patient management and outcomes. Additionally, a prospective cohort study reported that use of PCR-based testing in Lyme disease evaluation did not improve thediagnosis compared to standard 2-tiered testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are suspected of having Lyme disease who receive CXCL13 chemokine concentration testing, the evidenceincludes a meta-analysis of 18 studies of European cohorts and a US-based retrospective study. Relevant outcomes are a change indisease status and morbid events. Study results have demonstrated a high specificity and strong correlation with B. burgdorferi-specific antibody responses in patients with acute Lyme neuroborreliosis. However, there is wide variability in studies in defining a threshold for a significantly elevated CXCL13 value, which makes clinical performance characteristics unclear. Additional research is needed to determine the diagnostic utility of CXCL13 levels. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are suspected of having Lyme disease who receive stand-alone C6 peptide assay testing, the evidence includes cohort studies. Relevant outcomes are a change in disease status and morbid events. Limited data have shown specificity is slightly lower with stand-alone C6 peptide testing compared to 2-tiered approaches. Additional research is needed to determine the diagnostic utility of stand-alone C6 testing. The evidence is insufficient to determine that the technology results in an improvement in the nethealth outcome.

For individuals with confirmed Lyme disease who receive prolonged or repeated courses of antibiotic therapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, change in disease status, morbid events, and health status measures. Oral antibiotics usually are adequate for treatment of Lyme disease, though in some persistent cases, a 2- to 4-week course of intravenous (IV) antibiotics may be appropriate. Evidence from RCTs has not shown a benefit to prolonged (>4 weeks) or repeat courses of oral or IV antibiotics. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

Practice Guidelines and Position Statements

Centers for Disease Control and Prevention

In 2019, the Centers for Disease Control and Prevention (CDC) updated its recommendations for the serological diagnosis of Lyme disease. In addition to the standard 2-tiered testing process (sensitive enzyme immunoassay [EIA] or immunofluorescence assay, followed by a western immunoblot assay for specimens yielding positive or equivocal results), a modified 2-test methodology can beused, which uses a second EIA in place of the western immunoblot assay. Specifically, the CDC noted that "[w]hen cleared by FDA [Food and Drug Administration] for this purpose, serologic assays that utilize EIA rather than western immunoblot assay in a two-testformat are acceptable alternatives for the laboratory diagnosis of Lyme disease."

Regarding treatment of Lyme disease, appropriate, oral antibiotics in the early stages of Lyme disease typically lead to rapid andcomplete recovery. In those with disseminated, non-cutaneous manifestations of Lyme disease, longer courses of antibiotics orintravenous treatment with antibiotics such as ceftriaxone may be required.

Infectious Diseases Society of America et al

 The Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology published guidelines on the prevention, diagnosis, and treatment of Lyme disease in 2020. Overall, antibody tests are considered first-line for diagnosisdue to their performance characteristics and availability of accessible, clinically validated assays. Serum antibody tests are recommended to be used in a standard 2-tiered testing protocol, in which an EIA or indirect fluorescent antibody test is followed by immunoglobulin M (IgM) and IgG immunoblots. A modified 2-tiered testing protocol, in which 2 different EIAs are performed sequentially or concurrently without the use of immunoblots can also be used. The overall predictive value of these tests are increased when correlated with specific signs and symptoms, patient history, and risk factors. Antibody testing is limited by false negatives, especially in patients who present with cutaneous symptoms only within 2 weeks after the development of the skin lesion. The guidance notes that nonserological methods have been developed, such as polymerase chain reaction (PCR) assays, but the clinically validity of these approaches is not clear, in part due to the lack of a FDA-cleared test for Lyme disease diagnosis. Additionally, the guidance states that "[m]easurement of CXCL13 has not been sufficiently studied or standardized to recommend at present.”

Association of Public Health Laboratories

In May 2021, the Association of Public Health Laboratories published a guidance on the suggested reporting language, interpretation,and guidance for serologic test results for Lyme disease. The standard 2-tiered testing and modified 2-tiered testing methods arerecommended for diagnosis of Lyme disease. In disseminated Lyme disease, standard 2-tiered testing has a high sensitivity (>87%)and specificity (99%) and can provide strong support for a diagnosis. The guidance also notes that "[s]ome laboratories offer tests thathave not been cleared by FDA (e.g., molecular tests, antibody tests on samples other than serum). Use of these tests is generally notrecommended, as their accuracy and clinical usefulness have not been adequately established."

National Institute for Health and Care Excellence

Guidance on Lyme disease from the National Institute for Health and Care Excellence (NICE) was published in 2018. NICE recommended that if “there is clinical suspicion of Lyme disease in people without erythema migrans,” “an enzyme-limked immunosorbent assay (ELISA) test for Lyme disease” should be offered. If the ELISA test is “positive pr equivocal,” an “immunoblot test” for Lyme disease should be performe. The NICE recommended oral antibiotics for the treatment of erythem migrans and/or nonfocal symptoms, and a 21-day course of IV antibiotics for Lyme disease affecting the central nervous or for Lyme carditis when the patients are hemodynamically unstable.

International Lyme and Associated Diseases Society

The International Lyme and Associated Diseases Society published guidelines in 2014 to address three clinical issues: the usefulness of antibiotic prophylaxis of tick bites, the effectiveness of erythema migrans treatment, and antibiotic retreatment in patients with persistent symptoms. The Society noted that the evidence on treatment of tick bites, erythema migrans rashes, and persistent manifestations is limited. Regarding the treatment of patients with persistent symptoms, the Society panel concluded that the evidence for retreatment is adequate to support retreatment, but is not strong enough to mandate treatment. The panel determined that there was no compelling evidence supporting withholding antibiotics from symptomatic patients, especially since there is a lack of alternative treatment options. Due to the number of clinical variables and the heterogeneity of the patient population, clinical judgment and patients’ values and goals should be considered when planning a treatment strategy.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Intravenous Antibiotic Therapy for Lyme Disease, Lyme Disease, Intravenous Antibiotic Therapy, B lymphocyte chemoattractant, C6 peptide ELISA, Chemoattractant CXCL13, CXCL 13, genotyping of B. burgdorferi, Lyme Disease, PCR based direct detection of B. burgdorferi in urine samples, phenotyping of B. burgdorferi, B. burgdorferi

APPROVED BY GOVERNING BODIES:

The FDA has cleared multiple enzyme immunoassay, immunofluorescent assay and Western Blot IgG and IgM tests through the 510(k) process. There are also commercially available laboratory- developed tests for serologic testing for Lyme disease. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

86617              Borrelia burgdorferi (Lyme disease) confirmatory test (e.g., Western blot or immunoblot) 

86618              Antibody; Borrelia burgdorferi (Lyme disease)          

87475              Infectious agent detection by nucleic acid; Borrelia burgdorferi, direct probe technique

87476              Infectious agent detection by nucleic acid; Borrelia burgdorferi, amplified probe technique

0041U             Borrelia burgdorferi, antibody detection of 5 recombinant protein groups, by immunoblot, IgM

0042U             Borrelia burgdorferi, antibody detection of 12 recombinant protein groups, by immunoblot, IgG

REFERENCES:

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  21. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. Jan 23 2021; 72(1):e1-e48.
  22. Lipsett SC, Branda JA, McAdam AJ, et al. Evaluation of the C6 Lyme enzyme immunoassay for the diagnosis of Lyme disease in children and adolescents. Clin Infect Dis. Jun 28 2016.
  23. Mead P, Petersen J, Hinckley A. Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep. Aug 16 2019; 68(32): 703.
  24. Mygland A, Ljostad U, Fingerle V et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 2010; 17(1):8-16, e1-4.
  25. National Institute for Health and Care Excellence (NICE). Lyme disease [N95] 2018; Available at: www.nice.org.uk/guidance/NG95.
  26. Nigrovic LE, Lewander DP, Balamuth F, et al. The Lyme Disease Polymerase Chain Reaction Test Has Low Sensitivity. Vector Borne Zoonotic Dis. Apr 2020; 20(4): 310-313.
  27. Oksi J, Marjamaki M, Nikoskelainen J, et al. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med 1999; 31(3):225-32.
  28. Oksi J, Nikoskelainen J, Hiekkanen H, et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: A double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis 2007; 26(8):571-81.
  29. Pritt BS, Mead PS, Johnson DKH, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis. May 2016; 16(5): 556-564.
  30. Rupprecht TA, Manz KM, Fingerle V, et al. Diagnostic value of cerebrospinal fluid CXCL13 for acute Lyme neuroborreliosis. A systematic review and meta-analysis. Clin Microbiol  Infect. Dec 2018; 24 (12): 1234-1240.
  31. Sanchez E, Vannier E, Wormser GP, et al. Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and sabesiosis: a review. JAMA. Apr 26 2016; 315(16):1767-1777.
  32. Situm M, Poje G, Grahovac B, et al. Diagnosis of Lyme borreliosis by polymerase chain reaction. Clin Dermatol 2002; 20(2):147-55.
  33. Steere AC. Lyme disease.  N Engl J Med 2001; 345(2):115-25.
  34. Wilske B, Fingerle V and Schulte-Spechtel U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol Med Microbiol 2007; 49(1):13-21.
  35. Wormser GP, Dattwyler RJ, Shapiro ED, et al. 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 2006; 43(9):1089-134.
  36. Zannoli S, Fantini M, Semprini S, et al. Multicenter Evaluation of the C6 Lyme ELISA Kit for the Diagnosis of Lyme Disease. Microorganisms. Mar 24 2020; 8(3).

POLICY HISTORY:

Medical Policy Group, June 2009 (3)

Medical Policy Administration Committee, July 2009

Available for comment July 1-August 14, 2009

Medical Policy Group, January 2011 (3)

Medical Policy Administration Committee, January 2011

Available for comment January 11, 2011 through February 21, 2011

Medical Policy Group, March 2012 (3): Updates to Description, Policy, Key Points, References: Updated Guidelines and “Other Diagnostic Testing” as investigational

Medical Policy Administration Committee, March 2011

Available for comment March 28 through May 15, 2012

Medical Policy Group, October 2012 (3): Update to Description, Key Points and References

Medical Policy Panel, January 2014

Medical Policy Group, January 2014 (3): Update to Key Points and References; no change in policy statement

Medical Policy Panel, January 2015

Medical Policy Group, January 2015 (3): 2015 Updates – Key Points, Approved by Governing Bodies and References; no changes in policy statement.

Medical Policy Panel, October 2015

Medical Policy Group, October 2015 (6): Updates to Key Points, Key Words, Approved Governing Bodies, and References. Added “CSF abnormalities” to policy statement. Policy intent unchanged. Policy Retired.

Medical Policy Panel, October 2016

Medical Policy Group, November 2016 (3): 2016 Updates to Description, Key Points, & References; investigational indication clarification added to Policy statement but did not change policy statement intent.

Medical Policy Group, May 2017 (3):  Verbiage clarification on CPT code 87476; no policy statement changes

Medical Policy Group, July 2017 (3):  Verbiage clarification on policy statements related to “Polymerase chain reaction (PCR)-based direct detection of B. burgdorferi” - adding “(by direct or amplified probe)”; no other changes  

Medical Policy Panel, October 2017

Medical Policy Group, November 2017 (3): 2017 Minor updates to Description, Key Points & Approved by Governing Bodies. No new references added and no change to policy statement.

Medical Policy Group, December 2017: Annual Coding Update.  Created Previous Coding section and moved deleted CPT code 87477 to this section.

Medical Policy Panel, October 2018

Medical Policy Group, December 2018 (2): 2018 Policy review; minor updates to Key Points (updated Practice Guidelines and Poistion Statements), added 2 References; no change to Policy Statement.

Medical Policy Panel, October 2019

Medical Policy Group, November 2019 (2): Updates to Key Points, no change in policy statement.

Medical Policy Panel, October 2020

Medical Policy Group, October 2020 (2): Updates to Key Points and Reference; no change in Policy Statement.

Medical Policy Group, February 2021 (2): Updates to Policy Statement includes criteria for one repeat 2-to 4-week course of IV antibiotic therapy and option for second EIA/ELISA testing to confirm diagnosis, myopericarditis added as indication for Lyme arthritis; codes 0041U and 0042U added to coding section.

Medical Policy Panel, October 2021

Medical Policy Group, October (2): Updates to Key Points and References; verbiage clarification in Policy statement Antbiotic-refractory changed to post antibiotic therapy; no change in intent. CPT code 86618 added to Coding section.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.