CAM 159

Lyme Disease Testing

Category:Laboratory   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:February 2017    

Lyme disease is the most common tick-borne illness in the United States. Lyme disease is caused by the bacterium Borrelia burgdorferi and is transmitted to humans through the bite of infected blacklegged ticks, commonly known as deer ticks. Lyme disease manifests itself as a multisystem inflammatory disease that affects the skin in its early, localized stage, and spreads to the joints, nervous system and other organ systems in its later, disseminated stages.

Lyme disease is caused by four main species of bacteria: Borrelia burgdorferi, Borrelia mayonii, Borrelia afzelii and Borrelia garinii bacteria. Borrelia burgdorferi and Borrelia mayonii cause Lyme disease in the United States, while Borrelia afzelii and Borrelia garinii are the leading causes of Lyme disease in Europe and Asia.

Ticks can attach to any part of the human body, but are often found in hard-to-see areas such as the groin, armpits and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the Lyme disease bacterium can be transmitted. Most humans are infected through the bites of immature ticks called nymphs. Nymphs are tiny (less than 2 mm) and difficult to see; they feed during the spring and summer months. Adult ticks can also transmit Lyme disease bacteria, but they are much larger and are more likely to be discovered and removed before they have had time to transmit the bacteria.

Approximately 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 reported to CDC (CDC, 2016).

Symptoms of Lyme Disease
According to Moore et al. (2015) and UpToDate (2017), there are 3 stages of B. burgdorferi infection: early localized, early disseminated and late or chronic disease.

Early localized disease (occurring a few days to a month after the tick bite)

  • Fever, headache, fatigue, malaise, lethargy, myalgia, arthralgia, mild neck stiffness, regional lymphadenopathy
  • Erythema Migrans 
    • Classic sign of localized infection, occurring in approximately 80% of infected persons
    • Gradually expanding lesion reaching up to 12 inches or more in diameter
    • Often clears centrally as it enlarges, resulting in a bull’s eye appearance
    • They are not particularly painful, although EM lesions may occasionally burn or itch, and are hot to the touch

Early disseminated disease (occurring weeks to months after tick bite)

  • Carditis: manifestations include AV nodal block, mild cardiomyopathy or myopericarditis
  • Neurologic disease: manifestations include lymphocytic meningitis, cranial neuropathy, peripheral neuropathy; rarely myelitis or encephalitis
  • Musculoskeletal involvement: manifestations include migratory arthralgias
  • Eye involvement: conjunctivitis, iritis, choroiditis, vitritis, retinitis 
  • Lymphadenopathy: regional or generalized

Late or chronic disease (occurring months to years after tick bite)

  • Musculoskeletal: approximately 60 percent of untreated patients develop intermittent monoarticular or oligoarticular arthritis; approximately 10 percent of untreated patients develop persistent monoarthritis, usually affecting the knee
  • Neurologic disease: Peripheral neuropathy or encephalomyelitis 

Post–Lyme Disease Syndromes
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 (UpToDate, 2017).

Wormser et al. (2006) 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 Infectious Diseases Society of America (IDSA) has proposed a definition of post-Lyme disease syndrome. Criteria for this syndrome include a prior history of Lyme disease treated with an accepted regimen and resolution or stabilization of the objective manifestations of Lyme disease. In addition, the onset of subjective symptoms (e.g., fatigue, widespread musculoskeletal pain, complaints of cognitive difficulties) must have occurred within six months of the diagnosis of Lyme disease and persist (continuously or relapsing) for at least six months after completion of antimicrobial therapy (UpToDate, 2017). However, there is no evidence that persistent subjective symptoms after antibiotic treatment respond to antibiotic courses longer than those that are recommended. In addition, Lyme disease should never be a diagnosis of exclusion to explain puzzling complaints, particularly when they are not accompanied by objective markers of organ damage and/or inflammation (UpToDate, 2017).

Diagnosis and Testing
Per CDC (2016), laboratory blood tests are helpful if used correctly and performed with validated methods. Laboratory tests are not recommended for patients who do not have symptoms typical of Lyme disease.

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. However, the results of blood tests for Lyme disease can vary from laboratory to laboratory. Results can be difficult to interpret if there is no history of tick exposure or EM (Uptodate, 2017)

According to UpToDate (2017), the diagnosis of early Lyme disease can be made solely on clinical grounds if the characteristic erythema migrans (EM) lesion is present in a patient who lives in or has recently traveled to an area that is endemic for Lyme disease. The patient with a characteristic EM lesion will likely be seronegative, since the lesion appears prior to development of a diagnostic, adaptive immune response. Laboratory testing is neither required nor recommended.

Per Halperin et al. (2013), extra-cutaneous manifestations of Lyme disease are far less specific. As an example, facial nerve palsy is considered one of the more common clinical manifestations. The annual incidence of Bell's palsy (idiopathic facial nerve palsy) is estimated at 23/100,000; about 1% of cases are bilateral (0.23/100,000) (Ronthal M, 2012).

In highly endemic areas, where Lyme disease incidence reaches 300/100,000, the number of patients with Lyme disease-related unilateral facial nerve palsies might be expected to reach 24/100,000, equal to the background rate of Bell's palsy — that is, the positive predictive value of a unilateral facial nerve palsy would still be only 50%, mandating the use of a confirmatory laboratory test before treatment (Terushkin et al., 2010).

On serologic tests of Lyme disease, Halperin et al. (2013) state that, although there is ample evidence that seronegative early Lyme disease is not uncommon, the evidence of seronegative late Lyme disease is unconvincing and the concept lacks biologic plausibility.

Schriefer (2015) summarizes that serology is the mainstay of confirmation of Lyme borreliosis; direct detection has limited application. Because standardized 2-tier testing (STTT) has been commonly used since the mid 1990s, standardization and performance have improved. STTT detection of early, localized infection is poor; that of late disease is good. The best indicator of stage 1 infection, erythema migrans, is present in the majority of U.S. cases and should prompt treatment without testing. Clinical and epidemiologic correlates should be carefully assessed before ordering STTT. STTT has great value in confirming extra-cutaneous infection.

Blood tests for Lyme disease are not recommended in people with nonspecific symptoms, since tests may be falsely positive. Blood testing is also not recommended for a person who has classic features of early localized Lyme disease, including erythema migrans. Testing may be falsely negative during the first several weeks of infection, potentially delaying the correct diagnosis and treatment (UpToDate, 2017).

Serological tests —There are two major categories of blood tests: enzyme-linked immunosorbent assay (ELISA) and Western blot, which are used to check for current or prior infection with B. burgdorferi. The antibodies decline slowly after adequate antibiotic treatment; however, for certain patients, they can remain positive for years. Thus, a positive test result does not prove that the person has active infection (UpToDate, 2017).

Serologic testing should be performed in patients who meet all of the following criteria: A recent history of having resided in or traveled to an area endemic for Lyme disease and a risk factor for exposure to ticks and symptoms consistent with early disseminated disease or late Lyme disease (e.g., meningitis, radiculopathy, mononeuritis, cranial nerve palsy, arthritis, carditis) (UpToDate, 2017)

Serologic testing for Lyme disease should not be performed in the following settings (UpToDate, 2017):

  • 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.
  • For screening of asymptomatic patients living in endemic areas.
  • For patients with non-specific symptoms only (e.g., 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.

ELISA — The ELISA is usually the first test done for Lyme disease. The ELISA test is very sensitive at detecting antibodies to Lyme disease, but has low specificity. Because of the chance of the ELISA giving a false positive result, a Western blot, which has improved specificity, is typically ordered to confirm a positive ELISA test. If the ELISA is negative, the sample needs no further testing. ELISA tests are available for IgM (early), IgG (late) and combined IgM and IgG antibody detection.

Western blot — Western blot is done when the ELISA results are positive or equivocal because it is more specific for B. Bungdorferi and is helpful in determining if the results of an ELISA test are falsely positive. Western blots can be performed to detect either IgM or IgG antibodies.  

Cerebrospinal fluid tests — When a diagnosis of Lyme disease is uncertain and an individual has neurologic symptoms, testing the cerebrospinal fluid using the ELISA and western blot can help to confirm the diagnosis (Uptodate, 2016). 

Table 1: Sensitivity and Specificity of Serologic tests for patients with Lyme disease, USA (Moore et al., 2016), CDC (2016)

Variable Standard 2-tiered algorithm with whole-cell sonicate EIA+ Standard 2-tiered algorithm with C6 EIA, Wormser et al. Two-EIA algorithm
Molins et al. (CDC Lyme Repository Wormser et al. Branda et al. Branda et al. Wormser et al.
% Sinsitivity (no. tested)
Early Lyme disease with EM          
Acute phase  40 (40) 38 (298) 42(114) 38 (298) 53 (114) 58 (298)
Convalescent Phase 61 (38) 27 (105) 57 (63) 26 (105) 89 (63) 67 (105)
Noncutaneous manifestations 96 (46) 94 (142) 87 (55) 93 (142) 100 (55) 97 (144)
Early disseminated Lyme disease 88 (17) 80 (20) 73 (26) 80 (20) 100 (26) ND
Late disseminated Lyme disease 100 (29) 96 (122) 100 (29) 95 (122) 100 (29) ND
% Specificity (no. tested)
Healthy controls            
Endemic area 98 (101) 99 (1,329) 99 (1,146) 99 (1,329) 99 (1,146) ≥99 (1329)**
Nonendemic area 100 (102) 100 (513) 100 (100) 100 (513) 100 (100 ≥99 (513)**
Controls with selected other diseases
Syphilis or RPR postive 95 (20) 95 (20) ND 95 (20) ND ≥95 (20)**
Infectious mononucleosis or EBV/CMV positive 90 (30) 100 (40) ND 100 (40) ND 100 (20)
Helicobacter pylori ND 95 (20) ND 100 (20) ND 100 (20)
All nonhealthy controls 97 (144) 99 (366) 100 (54) 100 (366) 100 (54) 100 (366)+

Table 2: Per American Association of Clinical Chemistry (2016), the following table summarizes results that may be seen with Lyme disease antibody tests:

IgM Antibody IgG Antibody Western Blot Likely Interpretation
Positive Positive Positive Likely Lyme disease if consistent with other signs and symptoms
Positive Negative Negative Early infection or false-positive IgM test due to cross reactive antibodies
Negative Positive Positive Late or previous infection
Negative Negative (usually not performed if IgM and IgG are negative No infection present; symptoms may be due to another cause or antibody levels are too low to detect
Negative Positive Negative Patient has recovered from prior infection or false-positive IgG test due to cross reactive antibodies.

Polymerase Chain Reaction
Polymerase chain reaction (PCR) has been used clinically to identify the presence of B. burgdorferi DNA in CSF or synovial fluid specimens. PCR test results for B. burgdorferi are often positive in synovial fluid prior to antibiotic therapy. According to UpToDate (2017), there are several limitations to the use of PCR:

  • The accuracy of PCR is highly dependent upon the care used in sample collection and storage and the technique used in the assay.
  • False positive results are common. In particular, a positive CSF PCR is likely to be a false positive result in patients who are seronegative for Lyme disease. 
  • CSF PCR has low sensitivity. Thus, a negative PCR result does not exclude either neurologic Lyme disease or Lyme arthritis. 
  • PCR testing of specimens of CSF or synovial fluid for B. burgdorferi DNA in a reliable laboratory can add confirmatory information in seropositive patients. However, a positive PCR result by itself is likely to be a false positive result, and a positive result does not prove that the patient has active infection, since spirochetal DNA may persist long after spirochetal killing has occurred. PCR identifies DNA in the specimen; it does not differentiate between infection with a live organism and the presence of remnant DNA from a prior, but cured infection.
  • False negative PCR results can occur due to the presence of inhibitors of the DNA polymerase, such as hemoglobin or hyaluronic acid.
  • PCR of the urine is of no proven value in the diagnosis or management of B. burgdorferi infection in humans.

Regulatory Status 
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. 

Application of medical necessity criteria is dependent upon an individual’s benefit coverage at the time of the request 

  1. 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
  2. Serologic testing is considered NOT MEDICALLY NECESSARY in the following situations:
    • 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.
    • For screening of asymptomatic patients living in endemic areas.
    • For patients with non-specific symptoms only (e.g., 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.
  3. PCR-based direct detection of Borrelia burgdorferi is NOT MEDICALLY NECESSARY 
  4. Repeat PCR-based direct detection of Borrelia burgdorferi is considered INVESTIGATIONAL in the following situations
    • As a justification for continuation of IV antibiotics beyond one month in patients with persistent symptoms
    • As a technique to follow a therapeutic response
    • Via urine sample
  5. Other testing for Borrelia burgdorferi is considered INVESTIGATIONAL, including, but not limited to:
    • Genotyping and phenotyping
    • Determination of levels of the B lymphocyte chemoattractant CXCL13
  6. Testing of the individual tick is considered NOT MEDICALLY NECESSARY for the diagnosis of Lyme disease  

Policy Guidelines 
CDC (2016) 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


  1. American Association of Clinical Chemistry. (2014). Lyme disease testing challenges. Retrieved December, 2016, from CDC
  2. American Lyme Disease Foundation. (n.d). Retrieved December, 2016, from
  3. Halperin, J. J. (2015). Chronic Lyme disease: misconceptions and challenges for patient management. Infection and Drug Resistance, 8, 119–128.  
  4. Hu, L (2017). Clinical manifestations of Lyme disease in adults. Retrieved January, 2017, from
  5. Hu, L. (2017). Diagnosis of Lyme disease. Retrieved January, 2017, from
  6. Moore, A, Nelson, C, Molins, C, Mead, P, Schriefer, M. 2016. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of lyme disease, United States. 2016. Retrieved Devember, 2016, from
  7. Ronthal, M. (2015). Bell's palsy: pathogenesis, clinical features, and diagnosis in adults. Retrieved January, 2017, from
  8. Schriefer, M. (2015). Lyme disease diagnosis: serology; Clin Lab Med 2015 Dec;35(4):797-814. Retrieved January, 2017, from
  9. Terushkin, V., Stern, B.J., Judson, M.A. et al.(2010). Neurosarcoidosis: presentations and management. Neurologist. 2010; 16: 2–15
  10. 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 Two-Tier Testing for Lyme Disease. Diagnostic Microbiology and Infectious Disease, 75(1), 9–15.  

Coding Section 

Code Number Description
CPT 86617 Antibody; Borrelia burgdorferi (Lyme disease)
  86618 Antibody: Borrelia burgdorferi (Lyme disease confirmatory test (eg, Western Blot or immunoblot)
  87475  Infectious agent detection by nucleic acid (NDA or RNA); Borrelia Burgdorferi, direct probe technique. 
  87476  Infectious agent detection by nucleic acid (DNA 0r RNA); Borrellia 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 
  0043U  Tick-Borne Relapsing Fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgM 
  0044U  Tick-Borne Relapsing Fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgG 
ICD-10 Diagnoses  B65.0-B83.9  Helminthiases (parasitic diseases) 
  B85.0-B89  Pediculosis, acariasis and other infestations (parasitic diseases) 
  J30 (all codes)  Vasomotor and allergic rhinitis 
  L50 (all codes)  Urticaria 
  M25.5 Pain in joint
  R05  Cough 
  R06.02  Shortness of breath 
  R06.03 (effective 1/1/2018  Acute Respirtory distress 
  R06.2  Wheezing 
  R21 Rash and other nonspecific skin eruption
  R50.9 Fever, unspecified
  R51 headache
  R52 Pain, unspecified
  R53.83 Malaise and fatigue

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2017 Forward     


Annual review, no change to policy intent. Updating verbiage for clarity. Also updating coding. 


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