How do I diagnose a Lyme disease flare?

Diagnosing a Lyme Disease Flare

Critical Clarification: "Lyme Disease Flare" Is Not a Recognized Clinical Entity

There is no established diagnostic framework for a "Lyme disease flare" because this concept is not supported by current evidence-based guidelines. 1 Lyme disease follows a well-defined progression through early localized, early disseminated, and late disseminated stages—not a relapsing-remitting pattern with "flares." 1

What You May Actually Be Encountering

Post-Treatment Lyme Disease Syndrome (PTLDS)

• Some patients experience persistent nonspecific symptoms (fatigue, cognitive difficulties, sleep disturbance, personality changes) after appropriate antibiotic treatment for documented Lyme disease. 1
• These symptoms do not represent active infection or "flares"—they are post-infectious sequelae. 1, 2
• Serologic testing remains positive for months to years after successful treatment and cannot distinguish active infection from past infection. 1, 3
• Do not order repeat serologic testing after treatment completion, as persistent antibodies do not indicate active disease. 3

New or Inadequately Treated Infection

• If a patient with prior Lyme disease develops new objective findings (new erythema migrans, facial palsy, meningitis, carditis, or monoarticular arthritis), consider reinfection rather than "flare." 1
• Repeated infection with B. burgdorferi has been documented. 1
• Diagnosis requires the same clinical and serologic approach as initial infection, not monitoring of antibody titers. 1

Diagnostic Approach for Suspected New or Recurrent Lyme Disease

Step 1: Assess for Objective Clinical Findings

Do not pursue Lyme disease testing for nonspecific symptoms alone (fatigue, headache, myalgias, arthralgias without joint swelling). 1, 3 These have extremely low positive predictive value even in endemic areas. 1

Objective Findings That Warrant Evaluation:

• Erythema migrans: Expanding annular lesion >5 cm diameter developing 3–30 days after tick exposure. 1
• Neurologic: Lymphocytic meningitis, cranial neuropathy (especially facial palsy), radiculoneuritis, peripheral neuropathy, encephalopathy. 1
• Cardiac: Myocarditis, pericarditis with conduction abnormalities (especially atrioventricular block). 1, 3
• Musculoskeletal: Intermittent swelling and pain of large weight-bearing joints (especially knee), not just arthralgia. 1

Step 2: Verify Epidemiologic Plausibility

• Exposure history is the primary determinant of pretest probability. 1, 3
• Patients without recent tick exposure in endemic regions (Northeast, Upper Midwest) have positive predictive values as low as 10% for serologic testing. 1, 3
• Even in patients with arthritis, cranial neuropathies, or meningitis in non-endemic areas, only 0.7% actually have Lyme disease. 1, 3
• In low-pretest-probability scenarios, false-positive results are more likely than true positives. 1

Step 3: Apply Appropriate Diagnostic Testing

For Erythema Migrans:

• Diagnose clinically without laboratory testing if the patient has compatible exposure and typical rash. 1, 3
• Serologic testing is unnecessary and often negative during early localized disease (30–40% sensitivity). 1

For Suspected Disseminated Disease (Neurologic, Cardiac, Arthritic):

• Use two-tiered serologic testing: first-tier EIA or IFA, followed by reflex Western immunoblot only if first-tier is positive or equivocal. 1, 3
• For symptoms <4–6 weeks duration: IgM Western blot requires ≥2 of 3 specific bands (24 kDa, 39 kDa, 41 kDa). 3
• For symptoms >4–6 weeks duration: disregard IgM results (high false-positive rate) and rely only on IgG Western blot (≥5 of 10 specific bands). 3
• Sensitivity for disseminated disease is 70–100%; specificity is >95%. 1

For Suspected Neuroborreliosis:

• Order CSF analysis with cell count, differential, protein, and Lyme antibody index with concurrent serum sample for comparison. 3

For Suspected Lyme Arthritis:

• Consider synovial fluid or synovial biopsy for Lyme PCR if diagnosis is uncertain. 3

Step 4: Avoid Common Diagnostic Pitfalls

• Never order serologic testing as a screening tool in asymptomatic patients or those with only nonspecific symptoms. 1, 3
• Never use non-standard assays (urine antigen, CD57 tests)—these lack validation and are not recommended by any guideline. 3
• Never interpret persistent positive serology as evidence of active infection or "chronic Lyme disease." 1, 3
• Never order testing at the time of tick bite—antibodies are not yet detectable. 3
• Never order Western immunoblot without a positive first-tier test—this dramatically reduces specificity. 1, 3
• The 41-kDa band alone is not diagnostic—it cross-reacts with other bacterial flagellar proteins and appears in ~43% of healthy controls. 3

Treatment Considerations (If New Infection Is Confirmed)

• Early localized disease (erythema migrans): Doxycycline 100 mg orally twice daily for 10–14 days. 3
• Early disseminated disease (neurologic or cardiac): Doxycycline 100 mg orally twice daily for 14–21 days. 3
• Lyme arthritis: Doxycycline 100 mg orally twice daily for 28 days. 3
• Do not treat based solely on positive serology without objective clinical findings. 3

Alternative Diagnoses to Consider

• Southern tick-associated rash illness (STARI): EM-like rash in southeastern United States following Amblyomma americanum tick bite; infectious etiology unknown. 1, 3, 4
• Post-infectious sequelae: Persistent symptoms after documented and appropriately treated Lyme disease do not respond to additional antibiotics. 1
• Other tick-borne co-infections: Babesiosis, anaplasmosis, ehrlichiosis transmitted by Ixodes ticks. 3