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.

Confirmed Lyme Disease
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 antibiotics may be appropriate. Evidence from RCT s has not shown a benefit in prolonged (> 4 weeks) or repeat courses of oral or intravenous antibiotics. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

Additional Information
It is well established that the optimum method of testing for Lyme disease depends on the stage of the disease. Guidelines from the Centers for Disease Control and Prevention and other sources have supported policy statements related to a tiered diagnostic testing strategy. 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. When laboratory testing is indicated, 2-tiered serologic testing is recommended. The polymerase chain reaction may be clinically useful as a second approach in patients with a short duration of neurologic symptoms (< 14 days).

Objective
The objective of this evidence review is to evaluate whether the use of a specialized laboratory evaluation of individuals with suspected Lyme disease, and whether the use of repeated or prolonged courses of antibiotic therapy in individuals diagnosed with Lyme disease, improves the net health outcome.

Background   
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.

Treatment of Lyme Disease
Recommended treatment regimens are based on the stage and manifestations of Lyme disease.⁶ 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. 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.

Regulatory Status 
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 (CLIA).

Policy:
Treatment of LD consists of oral antibiotics, except for the following indications:
I. A 2- to 4-week course of IV antibiotic therapy may be considered MEDICALLY NECESSARY in patients with Lyme disease-associated meningitis, cranial neuropathy, radiculoneuropathy or with other peripheral nervous system (PNS) manifestations, we recommend using intravenous (IV) ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials (strong recommendation, moderate-quality evidence). The preferred antibiotic duration is 14–21 days.

Objective neurologic findings include:

• Lymphocytic meningitis associated with CSF abnormalities.
• Cranial neurophathy, other than uncomplicated cranial nerve palsy, with documented CSF abnormalities.
• Encephalitis or encephalomyelitis associated with 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 CNS infection, as indicated above.

Serologic documentation of infection requires:

• Positive or indeterminate enzyme-linked immunosorbent assay (ELISA).
• Positive immunoblot by CDC criteria.

Documented CSF abnormalities include ALL of the following:

• Pleocytosis
• Evidence of intrathecal production of B. burgdorferi antibodies in CSF
• Increased protein levels

II. A 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.

III. A single 2- to 4-week course of IV antibiotic therapy may be considered MEDICALLY NECESSARY in the small subset of patients 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.

IV. intravenous antibiotic therapy is considered NOT MEDICALLY NECESSARY in the following situations:

• Patients with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence for Lyme disease
• Patients with seronegative Lyme disease 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)
• Patients with vague systemic symptoms without supporting serologic or CSF studies
• Patients with a positive ELISA test, unconfirmed by an immunoblot or Western blot test (see definition above)
• Patients with an isolated positive serologic test in the setting of multiple negative serologic studies
• Patients with chronic (≥ 6 months) subjective symptoms ("post-Lyme syndrome") after receiving recommended treatment regimens for documented Lyme disease

V. Repeat or prolonged courses (e.g., greater than 4 weeks) of IV antibiotic therapy are considered NOT MEDICALLY NECESSARY.

NOTE: DIAGNOSTIC TESTING FOR LYME DISEASE IS ADDRESSED IN CAM 159.

Rationale 
This evidence review was created in January 1998 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Sept. 1, 2021.

Suspected Lyme Disease
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Prolonged or Repeated Courses of Antibiotic Therapy
Clinical Context and Therapy Purpose
The purpose of prolonged or repeated courses of antibiotic therapy in patients with confirmed Lyme disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of prolonged or repeated courses of antibiotic therapy improve the net health outcome of those with confirmed Lyme disease?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with confirmed Lyme disease.

Interventions
The therapy being considered is prolonged or repeated courses of antibiotic therapy.

Comparators
The following therapies are currently being used to treat confirmed Lyme disease: a standard course of oral antibiotic therapy and a 2- to 4-week course of intravenous antibiotic therapy.

Outcomes
The general outcomes of interest are disease remission and symptom reduction.

Follow-up over the long-term may be necessary to monitor for residual symptoms (e.g., joint inflammation, encephalopathy).

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
The evidence does not support the use of recommended antibiotic therapy to treat patients with persistent B. burgdorferi infection and well-documented Lyme disease.¹⁶ See Tables 3 and 4, which summarize the characteristics and results of blinded, RCTs of extended antibiotic therapy versus placebo in such patients. The evidence has provided inconsistent results.

While morphologic variants of B. burgdorferi are thought to be related to persistent Lyme disease symptoms, a systematic review by Lantos et al. (2014) found no evidence to support this thinking.¹⁷ Reviewers found no pathogenic relation between morphologic variants of B. burgdorferi and persistent symptoms of Lyme disease. Additionally, no literature was identified that would support a role for treatment of B. burgdorferi morphologic variants.

Table 3. Summary of Randomized Controlled Trial Characteristics: Prolonged Antibiotic Therapy

IgG: immunoglobulin G; IV: intravenous.

Table 4. Summary of Randomized Controlled Trial Results: Prolonged Antibiotic Therapy

BDI: Beck Depression Inventory; MCS: Mental Component Summary; MMPI: Minnesota Multiphasic Personality Inventory; PCS: Physical Component Summary; QOL: quality of life; SF-36: 36-Item Short-Form Health Survey; VAS: visual analog scale.

Section Summary: Prolonged or Repeated Courses of Antibiotic Therapy
Oral antibiotics usually are adequate for treatment of Lyme disease, though in some persistent cases, a 2- to 4-week course of intravenous antibiotics may be appropriate. Evidence from RCTs has not shown a benefit to prolonged (> 4 weeks) or repeat courses of oral or intravenous antibiotics.

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 a change in disease status and morbid events. PCR-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 the diagnosis 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 evidence includes a meta-analysis of 18 studies of European cohorts and a US-based retrospective study. Relevant outcomes are a change in disease 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 net health outcome.

For individuals with confirmed Lyme disease who receive prolonged or repeated courses of antibiotic therapy, the evidence includes 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 antibiotics may be appropriate. Evidence from RCTs has not shown a benefit in prolonged (> 4 weeks) or repeat courses of oral or intravenous antibiotics. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

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.⁵ 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 be used, 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-test format 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 and complete recovery.⁶ In those with disseminated, non-cutaneous manifestations of Lyme disease, longer courses of antibiotics or intravenous 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 2020.³ Table 5 lists their recommendations regarding diagnosis and treatment for Lyme disease and its various manifestations. Overall, antibody tests are considered first-line for diagnosis due 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."

Table 5. Selected Recommendations for Lyme Diagnosis and Treatment

National Institute for Health and Care Excellence
Guidance on Lyme disease from NICE was published in 2018.²⁶ The NICE recommended that if “there is clinical suspicion of Lyme disease in people without erythema migrans,” an “enzyme-linked immunosorbent assay (ELISA) test for Lyme disease” should be offered. If the enzyme-linked immunosorbent assay test is “positive or equivocal,” an “immunoblot test” for Lyme disease should be performed. The NICE recommended oral antibiotics for the treatment of erythema migrans and/or nonfocal symptoms, and a 21-day course of IV antibiotics for Lyme disease affecting the central nervous system or for Lyme carditis when the patients are hemodynamically unstable.

International Lyme and Associated Diseases Society
In 2014, the International Lyme and Associated Diseases Society published guidelines to address 3 clinical issues: the usefulness of antibiotic prophylaxis of tick bites, the effectiveness of erythema migrans treatment, and antibiotic retreatment in patients with persistent symptoms.²⁷ 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 concluded that the evidence for retreatment is adequate to support retreatment, but is not strong enough to mandate treatment. The Society 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

Ongoing and Unpublished Clinical Trials
Some currently ongoing or unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT: national clinical trial.
^a Industry sponsored or partially sponsored.

References: 

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2. Institute of Medicine (IOM). Critical Needs and Gaps in Understanding: Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: National Academies Press; 2011.
3. 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. PMID 33417672
4. Situm M, Poje G, Grahovac B, et al. Diagnosis of Lyme borreliosis by polymerase chain reaction. Clin Dermatol. Mar-Apr 2002; 20(2): 147-55. PMID 11973049
5. 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. PMID 31415492
6. Centers for Disease Control and Prevention. Lyme Disease: Treatment. Updated August 23, 2021; https://www.cdc.gov/lyme/treatment/index.html. Accessed September 2, 2021.
7. Oksi J, Marjamaki M, Nikoskelainen J, et al. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med. Jun 1999; 31(3): 225-32. PMID 10442678
8. 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. PMID 31821110
9. 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. PMID 26856777
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11. 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. PMID 29674128
12. Eckman EA, Clausen DM, Herdt AR, et al. Specificity and Diagnostic Utility of Cerebrospinal Fluid CXCL13 in Lyme Neuroborreliosis. Clin Infect Dis. May 18 2021; 72(10): 1719-1726. PMID 32221538
13. Sanchez E, Vannier E, Wormser GP, et al. Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. JAMA. Apr 26 2016; 315(16): 1767-77. PMID 27115378
14. 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. Oct 01 2016; 63(7): 922-8. PMID 27358358
15. 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). PMID 32213811
16. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jul 03 2007; 69(1): 91-102. PMID 17522387
17. Lantos PM, Auwaerter PG, Wormser GP. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin Infect Dis. Mar 2014; 58(5): 663-71. PMID 24336823
18. Berende A, ter Hofstede HJ, Vos FJ, et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med. Mar 31 2016; 374(13): 1209-20. PMID 27028911
19. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. Mar 25 2008; 70(13): 992-1003. PMID 17928580
20. Cameron D. Severity of Lyme disease with persistent symptoms. Insights from a double-blind placebo-controlled clinical trial. Minerva Med. Oct 2008; 99(5): 489-96. PMID 18971914
21. 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. Aug 2007; 26(8): 571-81. PMID 17587070
22. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help?. Neurology. Jun 24 2003; 60(12): 1916-22. PMID 12821733
23. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. Jul 12 2001; 345(2): 85-92. PMID 11450676
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25. Association of Public Health Laboratories. Suggested Reporting Language, Interpretation and Guidance Regarding Lyme Disease Serologic Test Results. May 2021; https://www.aphl.org/aboutAPHL/publications/Documents/ID-2021-Lyme-Disease-Serologic-Testing-Reporting.pdf. Accessed September 2, 2021.
26. National Institute for Health and Care Excellence (NICE). Lyme disease [NG95]. 2018; https://www.nice.org.uk/guidance/NG95. Accessed September 2, 2021.
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