What are the laboratory tests and treatment options for Lyme disease?

Lyme Disease Laboratory Testing

For patients with erythema migrans in endemic areas, diagnose clinically without laboratory testing and treat immediately—serologic testing is unnecessary and often falsely negative in early disease. 1

When to Test vs. When to Diagnose Clinically

Clinical Diagnosis Without Testing (Preferred in Early Disease)

• Erythema migrans (EM) in endemic areas requires no laboratory confirmation—approximately 70-80% of Lyme disease patients present with this pathognomonic rash, and serologic testing has poor sensitivity (only 30-40%) during the early infection window period. 1
• Accompanying symptoms may include fever, lymphadenopathy, myalgias, or arthralgias, but the presence of EM alone is sufficient for diagnosis and treatment. 1
• Geographic exposure history is the single most crucial factor—even highly specific tests produce false-positives when pretest probability is low. 1

When Laboratory Testing Is Indicated

• Order serologic testing only for suspected disseminated disease (neurologic symptoms, carditis, arthritis) or when EM is absent and clinical suspicion exists based on endemic exposure. 1
• In endemic areas or with recent travel to endemic areas, particularly when exposure history is suggestive, Lyme serology should be obtained. 2
• Never test patients from non-endemic areas without travel history—in low-incidence states, positive predictive value is only 10%, and only 0.7% of patients with arthritis, cranial neuropathies, or meningitis actually have Lyme disease. 1

The Two-Tiered Testing Algorithm

First-Tier Test: EIA or IFA

• Always begin with enzyme-linked immunoassay (EIA/ELISA) or immunofluorescence assay (IFA)—these highly sensitive screening tests measure overall IgM and IgG antibody response to B. burgdorferi antigens. 2
• Most laboratories use whole-cell sonicate preparation, though newer FDA-cleared EIAs using VlsE or C6 peptide antigens offer higher specificity with similar sensitivity. 2
• EIA is preferred over IFA because it is more easily automated and provides quantitative values enabling objective cutoff criteria. 2

Second-Tier Test: Western Immunoblot

• Perform Western immunoblot ONLY if first-tier EIA/IFA is positive or equivocal—this reflex testing approach increases specificity to >98% while maintaining sensitivity. 2
• For samples drawn within 4 weeks of disease onset, test for both IgM and IgG antibodies by Western blot. 3
• For samples drawn more than 4 weeks after disease onset, test for IgG antibodies only. 3

Test Performance by Disease Stage

• Early localized disease with EM: Sensitivity only 40% in acute phase, improving to 61% in convalescent phase (3-4 weeks later). 1
• Disseminated disease (neuritis, carditis, arthritis): Sensitivity reaches 88-100% with specificity >95%. 2, 1
• Overall two-tiered testing: Sensitivity 70-100% and specificity >95% for disseminated Lyme disease. 2, 1

Critical Pitfalls to Avoid

Testing Errors That Increase False-Positives

• Never order Western immunoblot without first performing EIA/IFA—skipping the first tier dramatically increases false-positive rates and violates standard testing protocols. 1
• Do not order routine laboratory panels in patients with Bell's palsy or facial paralysis unless specific risk factors exist—this leads to unnecessary costs, false-positive workups, and patient anxiety. 2

Tests to Never Order

• Avoid urine antigen tests and CD57 tests—these lack validation and are not recommended by any major guideline. 1
• Do not retest patients after treatment—antibodies persist for months to years after successful treatment and do not indicate active infection or treatment failure. 1

Cross-Reactivity Causing False-Positives

• Syphilis or positive RPR: 5% of patients may have false-positive Lyme serology due to cross-reactivity between spirochetes. 4
• Epstein-Barr virus (EBV) and cytomegalovirus (CMV): 10% false-positive rate in patients with these infections. 5
• Rheumatoid factor and autoimmune diseases: Nonspecifically recognize B. burgdorferi proteins, causing false-positive results. 5
• Other spirochetal infections: Relapsing fever Borrelia and Treponema pallidum cause cross-reactions with Lyme serology. 5

Role of Diagnostic Imaging

Do not routinely perform diagnostic imaging for suspected Lyme disease—diagnosis relies on clinical findings and two-tiered serologic testing, not imaging. 6

When Imaging May Be Appropriate

• MRI of brain/spine: Only to rule out alternative diagnoses (stroke, tumors, demyelinating disease) in patients with suspected CNS involvement. 6
• Joint imaging (X-ray, ultrasound, MRI): May evaluate Lyme arthritis severity or exclude other causes of monoarticular/oligoarticular arthritis, but diagnosis remains clinical and serologic. 6
• Avoid imaging as screening tool—this leads to incidental findings, patient anxiety, unnecessary costs, and radiation exposure without diagnostic benefit. 6

Special Considerations for Bell's Palsy

• In endemic areas, Lyme disease causes facial paralysis in up to 25% of cases. 2
• For patients in endemic areas or with recent travel to endemic areas, draw Lyme serology, particularly when exposure history is suggestive. 2
• Use the standard two-tiered approach: screening ELISA/IFA followed by confirmatory Western blot if positive or borderline. 2
• Bilateral facial nerve paralysis is atypical of Bell's palsy and may warrant more extensive workup for alternative diagnoses. 2