What is the recommended diagnostic workup and treatment for a patient with suspected Lyme disease, including management of early localized, early disseminated, and late disease?

Lyme Disease: Diagnostic Workup and Treatment

Diagnostic Approach

For patients with erythema migrans (EM) in endemic areas, diagnose clinically without laboratory testing and initiate treatment immediately. 1

When to Test vs. When to Treat Clinically

• Do NOT test patients presenting with a lesion consistent with EM who live in or traveled to Lyme-endemic areas (Northeast, upper Midwest, northwest California) - clinical diagnosis alone is sufficient 1
• Serologic testing is indicated only for suspected disseminated or late disease manifestations without EM 1
• The classic EM rash appears in 70-80% of Lyme disease cases as a gradually expanding annular lesion >5 cm diameter 1

Two-Tiered Serologic Testing (When Indicated)

Use enzyme immunoassay (EIA/ELISA) or immunofluorescence assay (IFA) first, followed by reflex Western immunoblot only if the first test is equivocal or positive. 1

Critical Limitations of Serologic Testing:

• Sensitivity is only 30-40% during early localized disease due to the antibody window period 1
• Sensitivity improves to 70-100% for disseminated disease 1
• Specificity remains high (>95%) across all disease stages 1
• Antibodies persist for months to years after successful treatment - positive serology does NOT indicate active infection or treatment failure 1, 2, 3

Consider Coinfection

Suspect coinfection with Babesia microti or Anaplasma phagocytophilum if patients have high-grade fever persisting >48 hours despite appropriate antibiotics, or unexplained leukopenia, thrombocytopenia, or anemia. 1

Treatment by Disease Stage

Early Localized Disease (Erythema Migrans)

Treat with oral antibiotics for 14 days (range 14-21 days). 1

Preferred oral regimens:

• Doxycycline 100 mg twice daily 1
• Amoxicillin 500 mg three times daily 1
• Cefuroxime axetil (alternative) 1

Key points:

• Oral therapy is sufficient even for severe early manifestations 1
• Avoid doxycycline in pregnant or lactating patients - use amoxicillin instead 1
• Do NOT use ceftriaxone for early disease without neurologic involvement or advanced heart block 1

Early Disseminated Disease

Neurologic Manifestations:

For meningitis or radiculopathy: Use parenteral therapy for 14 days (range 10-28 days). 1

For isolated cranial nerve palsy (e.g., facial palsy): Oral regimen for 14 days (range 14-21 days) is sufficient. 1

• Neurologic manifestations include lymphocytic meningitis, cranial neuropathy (especially facial nerve palsy), and radiculopathy 1
• CNS involvement may include encephalomyelitis with focal neurologic abnormalities 1

Cardiac Disease:

Treat with oral OR parenteral regimen for 14 days (range 14-21 days) depending on severity. 1

• Cardiac manifestations include myocarditis and atrioventricular block 1
• Occurs in approximately 5% of cases 1

Multiple Erythema Migrans or Borrelial Lymphocytoma:

Oral regimen for 14 days (range 14-21 days). 1

Late Disseminated Disease

Lyme Arthritis:

For arthritis without neurologic disease: Oral regimen for 28 days. 1

For recurrent arthritis after oral therapy: Oral OR parenteral regimen for 14 days (range 14-28 days). 1

For antibiotic-refractory arthritis: Symptomatic therapy only. 1

• Late arthritis typically manifests as intermittent swelling and pain of large, weight-bearing joints (especially knees) 1
• Develops weeks to months after initial infection in untreated patients 1, 2

Late Neurologic Disease:

Parenteral regimen for 14 days (range 14-28 days). 1

• Manifestations include chronic axonal polyneuropathy or encephalopathy with cognitive disorders, sleep disturbance, fatigue, and personality changes 1, 2

Acrodermatitis Chronica Atrophicans:

Oral regimen for 21 days (range 14-28 days). 1

• This late skin manifestation develops 0.5-8 years after initial infection 2
• Begins with bluish-red discoloration and progresses to skin atrophy 1

Post-Treatment Considerations

Complete response to treatment may be delayed beyond the treatment duration - this is normal and does NOT indicate treatment failure. 1

Post-Lyme Disease Syndrome:

• Approximately 35% of patients have subjective symptoms at day 20,24% at 3 months, and 17% at 12 months after treatment 2, 3
• These symptoms reflect slow resolution of inflammatory processes, NOT persistent infection 2, 3
• Evaluate for other potential causes of symptoms; if none found, provide symptomatic therapy only 1

Relapse vs. Reinfection:

Patients with objective signs of relapse may need a second course of treatment, but distinguish true relapse from reinfection. 1

• Repeated infection with B. burgdorferi can occur - neither positive serology nor previous Lyme disease confers protective immunity 1, 2
• Clinical response, NOT serologic findings, should determine treatment success 2, 3

Critical Pitfalls to Avoid

DO NOT use these ineffective or harmful therapies: first-generation cephalosporins, fluoroquinolones, carbapenems, vancomycin, metronidazole, benzathine penicillin G, long-term antibiotic therapy, pulsed-dosing, combination antimicrobials, hyperbaric oxygen, or intravenous immunoglobulin 1

DO NOT misinterpret persistent antibodies as treatment failure or ongoing infection - this leads to unnecessary prolonged antibiotic courses 2, 3

DO NOT order serologic testing for patients with classic EM in endemic areas - this delays treatment and adds no diagnostic value 1

Tick Bite Prophylaxis

Single-dose doxycycline 200 mg (4 mg/kg in children ≥8 years) may be offered ONLY when ALL criteria are met: 1

1. Attached tick reliably identified as adult or nymphal Ixodes scapularis
2. Estimated attachment ≥36 hours based on engorgement
3. Prophylaxis can start within 72 hours of tick removal
4. Local tick infection rate with B. burgdorferi is ≥20%
5. Doxycycline not contraindicated