Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease

POLICY NUMBER

A.5.01.08

DESCRIPTION

Lyme disease 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), which may be followed by dissemination to many sites. Diagnostic testing for Lyme disease is challenging, and there is the potential for overdiagnosis and overtreatment.

Lyme Disease

Lyme disease is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi and transmitted by the bite of an infected Ixodes scapularis (northeastern region) or Ixodes pacificus (Pacific coast, most often in Northern California) tick. The disease is characterized by stages, beginning with localized infection of the skin (erythema migrans), followed by acute dissemination, and then late dissemination to many sites. Manifestations of the 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 Lyme disease 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 Lyme disease.

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. In patients with meningitis, the cerebrospinal fluid (CSF) will typically show a lymphocytic pleocytosis (lymphocyte count greater than normal) with increased levels of protein and normal glucose levels. Intrathecal production of antibodies directed at spirochetal antigens is also typically present. Other manifestations of early disseminated disease can include cranial neuritis (including unilateral or bilateral facial palsy) and peripheral nervous system manifestations. Cranial neuritis, most frequently Bell palsy, may present early in 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 disseminated stage of the disease; symptoms include atrioventricular (AV) block, tachyarrhythmias, and myopericarditis. The most common abnormality is fluctuating degrees of AV block.

Lyme Arthritis

Lyme arthritis is a late manifestation of infection and is characterized by an elevated immunoglobulin G (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

OverviewThe optimum method of testing for Lyme disease depends on the stage of the disease. Diagnostic testing may not be necessary when a 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), polymerase chain 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 (ie, 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, the 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. 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 with 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 one 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 TestsThe 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 immunoglobulin M (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. Immunoglobulin G antibodies produced in response to Lyme disease may persist for months or years. Thus detection of IgG antibodies only indicates exposure, either past or present. In Lyme disease-endemic areas, underlying asymptomatic seropositivity may range up to 5% to 10%. Thus, as with any laboratory test, interpretation of serologic tests requires a close correlation with the patient's signs and symptoms. For example, patients with vague symptoms of Lyme disease, chronic fatigue syndrome, or fibromyalgia may undergo multiple serologic tests over many weeks to months to establish the diagnosis of Lyme disease. 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 two-tiered method for the serologic diagnosis of Lyme disease. 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 (ELISA) for Borrelia Burgdorferi AntibodiesThis 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 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 a Western immunoblot or a second EIA. The overall predictive value is increased when correlated with the clinical picture.

Western ImmunoblotThis 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 the 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 the prevalence of different Borellia 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 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. Also, the test cannot distinguish between live spirochetes or fragments of dead ones. The PCR technique has been studied using various specimens. PCR has the best detection rates for skin biopsies from patients with erythema migrans(but who may not be indicated with a recent history of tick bite or exposure) and for synovial tissue (and synovial fluid, to a lesser extent) from patients with Lyme arthritis. Cerebrospinal fluid may be positive by PCR during the first two 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 of serologic 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 AssayT-lymphocyte proliferation assays, which detect responses of human mononuclear cells to borrelial antigens, 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 adjunct in identifying infections and as a potential marker for successful treatment. The Centers for Disease Control and Prevention notes that standardized interpretation criteria is required before this test can be recommended.

Borrelia Outer surface protein A

Antigen testing of urinary Borrelia Outer surface protein A (OspA) C-terminus peptide has been investigated using the Nanotrap® Antigen Test. This test employs Nanotrap particles to concentrate urinary OspA and uses a highly specific anti-OspA monoclonal antibody as a detector of the C-terminus peptides. Consistent with recommendations from the Centers for Disease Control and Prevention, the manufacturer of the Nanotrap® Antigen Test recommends using the Nanotrap® Antigen Test in conjunction with 2-tiered testing (ELISA with reflex to Western blot) for confirmation of a Lyme disease.

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 the 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. 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.

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.

POLICY

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

Neuroborreliosis

A 2- to 4-week course of intravenous (IV) antibiotic therapy may be considered medically necessary in individuals 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

• 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 by 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 ELISA test, AND

• Positive immunoblot by Centers for Disease Control and Prevention (CDC) criteria.

Documented CSF abnormalities include ALL of the following:

• Pleocytosis;

• Evidence of intrathecal production of B. burgdorferi antibodies in CSF; and

• Increased protein levels.

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

Lyme Carditis

A single 2- to 4-week course of IV antibiotics may be considered medically necessary in individuals 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 seconds. Documentation of Lyme carditis may include PCR-based direct detection of B. burgdorferi in the blood when results of serologic studies are equivocal.

Lyme Arthritis

A single 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in the small subset of individuals 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.

Antibiotic Therapy

Intravenous antibiotic therapy is considered investigational in the following situations:

• Individuals with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence of Lyme disease;

• Individuals with seronegative Lyme disease in the absence of CSF antibodies;

• Initial therapy in individuals with Lyme arthritis without coexisting neurologic symptoms;

• Cranial nerve palsy (eg, Bell 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);

• Individuals with vague systemic symptoms without supporting serologic or CSF studies;

• Individuals with a positive ELISA test, unconfirmed by an immunoblot or Western blot test (see definition above);

• Individuals with an isolated positive serologic test in the setting of multiple negative serologic studies.

• Individuals with chronic (greater than or equal to 6 months) subjective symptoms ("post-Lyme syndrome") after receiving recommended treatment regimens for documented Lyme disease.

Repeat or prolonged courses (greater than 4 weeks) of intravenous antibiotic therapy are considered investigational.

Diagnostic Testing

Repeat PCR-based direct detection of B. burgdorferi is considered investigational in the following situations:

• as a justification for continuation of IV 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 is considered investigational in all clinical situations.

Genotyping or phenotyping of B. burgdorferi is considered investigational.

Other diagnostic testing is considered investigational including but not limited to "stand-alone" C6 peptide ELISA, determination of levels of the B lymphocyte chemoattractant CXCL13, or Outer surface protein A (OspA) antigen testing for diagnosis or monitoring treatment.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

1/1994: Approved by Medical Policy Advisory Committee (MPAC).

5/1/2002: Type of Service and Place of Service deleted.

3/25/2004: Reviewed by MPAC, Policy title “Lyme Disease Treatment” renamed “Intravenous Antibiotic Therapy for Lyme Disease”, Description and Policy sections revised to be consistent with BCBSA policy # 5.01.08, intravenous antibiotic therapy changed from investigational to medically necessary for certain indications, investigation definition added, Sources updated, tables added to Code Reference section.

5/5/2004: Code Reference section completed.

3/13/2006: Policy reviewed, no changes.

9/12/2006: Coding reviewed. ICD9 2006 revisions added to policy.

11/13/2006: Code Reference section updated: CPT codes 87475, 87476, and 87477 deleted from policy.

4/24/2007: Policy reviewed, policy statement rewritten for clarification.

6/21/2007: Policy reviewed, description updated. Policy statement revised; IV antibiotic therapy is not medically necessary for uncomplicated cranial nerve palsy associated with Lyme disease and antibiotic-refractory Lyme arthritis.

7/19/2007: Reviewed and approved by MPAC.

7/10/2009: Policy reviewed, no changes.

12/15/2009: Coding Section revised with 2010 CPT4 and HCPCS revisions.

02/23/2011: Added the following to the policy statement: Determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment is considered investigational. No changes to other policy statements. Removed deleted HCPCS codes J0530, J0540, and J0550 from the Code Reference section.

02/24/2012: Add the following policy statement: A single 2- to 4-week course of IV antibiotics may be considered medically necessary in patients 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. The last policy statement was revised to state that other diagnostic testing is considered investigational including but not limited to C6 peptide ELISA or determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment. It previously stated that determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment is considered investigational. Deleted outdated references from the Sources section.

11/28/2012: Policy reviewed; no changes.

03/10/2014: Policy reviewed; no changes to policy statement. Removed deleted HCPCS codes J0560, J0570, and J0580 from the Code Reference section. Added HCPCS code J0561.

02/18/2015: Policy description updated regarding polymerase chain reaction and the evaluation of the Chemoattractant CXCL13. Medically necessary policy statement regarding PCR-based direct detection of B. burgdorferi in CSF samples updated to add "and may replace serologic documentation of infection" to the policy statement. Removed the following statement: PCR-based direct detection of B. burgdorferi in the blood when results of serologic studies are equivocal. Policy statement criteria on intravenous antibiotic therapy updated to state: Patients with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence for Lyme disease. Policy statements renumbered.

08/28/2015: Medical policy revised to add ICD-10 codes.

12/02/2015: Policy description updated regarding laboratory testing. Policy statements unchanged. Policy guidelines section updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.5.01.08 added.

01/01/2017: Code Reference section updated to add the following CPT codes: 87475, 87476, and 87477.

01/20/2017: Policy description updated regarding diagnostic tests. Investigational statement regarding C6 peptide ELISA updated to add "stand-alone."

10/30/2017: Policy description updated regarding laboratory-developed tests. Policy section updated to add section headings.

12/21/2017: Code Reference section updated to make note of deleted CPT code 87477 effective 12/31/2017.

03/28/2018: Code Reference section updated to add new CPT codes 0041U, 0042U, 0043U, and 0044U, effective 04/01/2018.

11/05/2018: Policy description updated. Policy statements unchanged.

11/19/2019: Policy reviewed; no changes. Code Reference section updated to remove deleted CPT code 87477.

11/20/2020: Policy description updated regarding Lyme disease. Policy statements unchanged.

01/17/2022: Policy description revised. Policy statement updated to change "antibiotic-refractory" to "post-antibiotic." Policy statement intent unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

09/21/2022: Code Reference section updated to make note of deleted ICD-10 diagnosis code.

05/01/2023: Policy description updated regarding Borrelia Outer surface protein A (OspA). Policy section updated to change "not medically necessary" to "investigational" and to add OspA antigen testing as investigational. Code Reference section updated to add CPT code 86619 as covered and CPT code 0316U as investigational.

11/14/2023: Policy reviewed. Policy statements updated to change "patients" to "individuals." Code Reference section updated to remove deleted ICD-10 diagnosis code G93.3.

01/09/2025: Policy reviewed; no changes.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis code R76.89.

SOURCE(S)

Blue Cross Blue Shield Association policy #5.01.08

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.