Diagnosis of early Lyme disease is made clinically by history and demonstration of EM. Serologic testing at this stage is often negative.  In early disseminated disease, patients will have positive IgM and IgG serologies.  IgG will be positive in patients with late disease.  

The two testing algorithm is recommended for serological testing.  A sensitive ELISA test is done first, followed by a specific western blot if needed. A negative initial ELISA does not require a western blot. A negative western blot supersedes a positive ELISA, and the test should be considered negative. Only 20-40% of patients with early disease test positive using the two-tier method; therefore, patients with typical EM lesions should be treated regardless of lab testing.15,, Patients treated with early or prophylactic antibiotics may not seroconvert. Successful treatment will decrease IgG and IgM antibodies, but they may remain elevated for years. In a study of 40 patients, 10-20 years post-infection, 10% had positive IgM, and 25% had positive IgG.  In these patient’s reinfection is typically diagnosed by new EM lesions, but a >3 fold increase in titers may occur.

Table 1 – Diagnostic Testing

Testing Method



It can neither completely include nor exclude the diagnosis.  Serology should be used in conjunction with physical findings and patient history. Serology should be performed in patients with recent travel history to an endemic area with risk factors for tick exposure.  Patients also must have symptoms consistent with early disseminated or late disease. Serology should not be performed in patients with EM, screening of asymptomatic patients, and patients with non-specific symptoms.16, IgM antibodies appear within 1-2 weeks following infection.  IgG antibodies appear within 1-6 weeks


Culture is not routinely done in clinical practice because growth is slow and requires a complex media


Spirochetes can be visualized by silver or immunofluorescence staining


PCR has been used to identify B. burgdoferi in synovial fluid and CSF.  Accuracy is highly dependent on proper specimen acquisition and handling. The sensitivity of PCR is low and false positives are common.  A positive PCR with negative serologies is most likely a false positive

Tick Testing

PCR is available to test ticks for B. burgdorferi; however, this is not routinely done clinically as it would not affect the management

Other lab abnormalities15

  • Elevated ALT or AST 37%, 
  • ESR > 2x ULN in 24%
  • Elevated CPK 12%
  • Leukocytosis 5%
  • Leukopenia 4%
  • Anemia 3%
  • Thrombocytopenia 1.5%

Table 2 – Differential Diagnosis

Disease State



A bite from Amblyomma americanum tick can cause a similar rash to EM.  Obtaining travel history is important to differentiate from Lyme.  The tick species domain can overlap, but high prevalence Lyme areas have a low incidence of STARI. STARI's systemic symptoms are mild and resemble influenza


Fibromyalgia is a diagnosis of exclusion; however, patients usually will not have a history of a tick bite.  Late Lyme disease also has evidence of organ inflammation and dysfunction, while fibromyalgia will not

Tick bite hypersensitivity

Lesions appear quickly and disappear within 24-48 hours. It can be distinguished from EM as EM gets bigger over time.  Lesions may appear urticarial and have accompanying pruritus

Nummular eczema

Circular, extremely pruritic papular, scaly, or crusted lesions.  It usually occurs in patients with a history of eczema or other atopic illnesses 

Tinea Corporis

A dermatophyte infection that causes a pruritic circular or oval patch or plaque. Lesions have a central clearing with raised erythematous borders


Infection of the deep dermis and subcutaneous fat that manifests with erythema, warmth, and pain.  Does not typically occur at usual sites for EM.

Granuloma Annulare

Papules or nodules grouped in a circular formation with raised borders

Erythema Multiforme

Acute eruptive skin disorder characterized by circular lesions.  Prodromal symptoms are absent and usually has a benign clinical course

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