What is the appropriate diagnostic workup and initial management for a patient being evaluated for Lyme disease?

Lyme Disease Diagnostic Workup

For patients with erythema migrans (EM) in an endemic area, diagnose clinically and treat immediately without laboratory testing; for all other presentations, use two-tiered serologic testing (EIA/IFA followed by Western blot) only when there is objective evidence of disseminated disease and appropriate epidemiologic exposure. 1

Clinical Diagnosis Without Laboratory Testing

Erythema migrans is the only manifestation that should be diagnosed and treated without serologic confirmation. 1

• The rash must be a gradually expanding annular lesion >5 cm in diameter, documented by an experienced clinician in a patient with plausible tick exposure in an endemic area 1
• Approximately 70-80% of Lyme disease patients present with EM 1
• Laboratory testing is unnecessary and may be misleading during early infection due to the antibody window period 1

Two-Tiered Serologic Testing Protocol

When laboratory testing is indicated, always use the complete two-tiered approach: first-tier EIA or IFA, followed by Western blot only if the first test is positive or equivocal. 1, 2

First-Tier Testing

• Order enzyme-linked immunoassay (EIA/ELISA) or immunofluorescence assay (IFA) as the initial screening test 1
• If negative and symptoms are present for <4 weeks, consider repeat testing in 2-4 weeks if clinical suspicion remains high 1

Second-Tier Western Blot Interpretation

• For disease duration <4 weeks: Interpret both IgM and IgG Western blots 2, 3
  • IgM positive requires ≥2 of 3 specific bands (24 kDa, 39 kDa, 41 kDa) 2
  • IgG positive requires ≥5 of 10 specific bands 2
• For disease duration >4 weeks: Only interpret IgG Western blot; disregard IgM results due to high false-positive rates 2, 3

Test Performance Characteristics

• Sensitivity during early localized disease: 30-40% (due to antibody window period) 1
• Sensitivity for disseminated disease: 70-100% 1
• Specificity: >95% when two-tiered testing is performed correctly 1

Indications for Laboratory Testing

Test only when there are objective clinical findings of disseminated disease with appropriate epidemiologic exposure. 1

Strong Indications (Test These Patients)

• Neurologic manifestations: Lymphocytic meningitis, cranial neuropathy (especially facial palsy), radiculoneuritis 1, 2
• Cardiac manifestations: Acute myocarditis/pericarditis with dyspnea, palpitations, chest pain, syncope, or conduction abnormalities (PR >300 ms) in endemic areas 1, 2
• Articular manifestations: Intermittent swelling and pain of large joints, especially the knee 1
• Multiple EM lesions (though single EM should be diagnosed clinically) 1

Do NOT Test These Patients

• Nonspecific symptoms without objective findings: Fatigue, myalgias, headache, paresthesias alone 1, 2
• Psychiatric illness 1
• Chronic cardiomyopathy of unknown cause 1
• Typical presentations of ALS, MS, Parkinson's disease, dementia, or new-onset seizures 1, 2
• Nonspecific MRI white matter abnormalities without other clinical support 1
• Patients without tick exposure or travel to endemic areas 2, 3

Pre-Test Probability Assessment

Pre-test probability determines whether testing is appropriate and how to interpret results. 2, 3

High Pre-Test Probability

• Endemic area exposure (Northeast, Upper Midwest US) during tick season 1
• Objective clinical findings consistent with disseminated Lyme disease 2, 3
• Recent tick bite or outdoor exposure in endemic region 2

Low Pre-Test Probability

• Non-endemic area without travel history 2
• No tick exposure 2
• Chronic symptoms lasting months without objective findings 2
• In non-endemic areas, positive predictive value of IgM is only ~10% (90% false-positives) 2
• Only 0.7% of patients with arthritis/neuropathy in low-incidence regions actually have Lyme disease 2

Additional Testing for Specific Manifestations

Neuroborreliosis

• CSF analysis with cell count, differential, protein 2
• CSF Lyme antibody index with concurrent serum sample for comparison 2
• Serum two-tiered testing 1

Lyme Carditis

• ECG for all patients with dyspnea, palpitations, chest pain, syncope, or lightheadedness 1
• Continuous cardiac monitoring for PR >300 ms or other arrhythmias 1
• Consider troponin and evaluation for pericardial effusion 1

Lyme Arthritis

• Serum antibody testing (preferred over PCR or culture) 1
• If seropositive but diagnosis uncertain, synovial fluid or tissue PCR 1

Critical Testing Pitfalls to Avoid

Never use unvalidated test methods or order testing in inappropriate clinical scenarios. 1

• Do not order: Urine antigen tests, blood microscopy for Borrelia, CD57 testing 1, 2
• Do not test: Asymptomatic patients or those at tick bite presentation 2
• Do not interpret: Western blot without a positive first-tier test 2
• Do not diagnose: Based on 41 kDa band alone (present in ~43% of healthy controls) 2
• Do not retest: After treatment completion, as antibodies persist for months to years 2
• Do not screen: Patients with low pre-test probability, as false-positives will outnumber true cases 1, 2

Laboratory Selection

Use only well-qualified laboratories that employ FDA-cleared, validated testing methods with CDC-recommended interpretive criteria. 1

• Ensure the laboratory follows standard two-tiered protocols 1, 2
• Verify proper Western blot band interpretation criteria 2
• Avoid laboratories offering non-standard or unvalidated assays 1

Initial Management Considerations

When to Treat Without Waiting for Test Results

• Typical EM in endemic area during appropriate season 1, 4
• High clinical suspicion for early disseminated disease with appropriate exposure 4

Antibiotic Selection Based on Manifestations

• Early localized disease (EM): Doxycycline 100 mg PO twice daily for 10-14 days 4, 5
• Early disseminated disease: 14-21 days of oral antibiotics 4
• Lyme arthritis: 28 days of oral antibiotics 1, 4
• CNS involvement: IV antibiotics 1, 4
• Lyme carditis (outpatient): Oral antibiotics; (hospitalized) initial IV ceftriaxone until improvement, then oral completion for total 14-21 days 1, 4

Co-infection Evaluation

• Consider testing for Babesia, Anaplasma, and Ehrlichia in patients with confirmed Lyme disease from endemic areas 2