Lyme Disease Differential Diagnoses

Updated: May 17, 2023
  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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Diagnostic Considerations

In most patients with erythema migrans, a carefully elicited history (including definitions of epidemiologic context) and a physical examination are all that is required to establish the diagnosis of Lyme disease. However, although many patients with Lyme disease present with erythema migrans, others first present with extracutaneous symptoms. In those cases, erythema migrans may never have occurred, may not have been recognized by the patient, or may not have been correctly diagnosed by the physician.

There can be a tendency to overdiagnose Lyme disease, especially in patients with a lifestyle that puts them in a high-risk category. Performing tests when the prior probability of disease is low increases the likelihood of false-positive results. The best way to avoid problems with diagnosis is to follow the Centers for Disease Control and Prevention (CDC) guidelines regarding diagnosis (see Workup), to use a reputable laboratory with experience in testing for Lyme disease, and to obtain the assistance of an infectious disease expert when any questions arise.

Because interpretation of testing is related to stage of disease and requires a two-stage test, laboratory results are often misinterpreted. Clinicians unfamiliar with Lyme disease or Lyme testing may falsely exclude the diagnosis by testing too early in the disease course, or falsely diagnose disease by following up negative enzyme immunoassay (EIA) results with Western blot testing (the latter is indicated only in patients with a positive or indeterminate EIA result).

In addition, separating false-positive antibody tests from asymptomatic infection is impossible. Approximately 5-10% of patients in endemic areas have positive antibody results without a history of symptoms.

Unfortunately, antibodies induced by the infection are not protective against further exposures to Borrelia burgdorferi; therefore, reinfection easily could be confused with a recurrence. Because antibodies may persist for years following an infection, repeat infection is a difficult diagnosis without specific signs of Lyme disease (eg, erythema migrans). Increasing titers after adequate treatment certainly raises suspicion of an active infection, but this is not a reason to repeat posttreatment titers, as they may remain positive for many years.

Other problems to be considered include the following:

  • Ankylosing spondylitis and rheumatoid arthritis
  • Atrioventricular (AV) nodal block
  • Cellulitis (see image below)Contact dermatitis
  • Granuloma annulare
  • Confusional states and acute memory disorders
  • Gout and pseudogout
  • Prion-related diseases
  • Lyme disease. The rash on the ankle seen in this p Lyme disease. The rash on the ankle seen in this photo is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (presentation in July, in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin-clavulanate) is an effective strategy.


The pathogens responsible for babesiosis and ehrlichiosis share the same tick vector as B burgdorferi, making co-infection possible. Severe and even fatal acute infection caused by these pathogens is more common in asplenic individuals (babesiosis) or older adults (ehrlichiosis). Unlike B burgdorferi, however, these pathogens do not cause chronic infection. To add to the confusion, ehrlichial infection may cause a false-positive result for Lyme disease on immunoglobulin M (IgM) Western blot analysis.

In a prospective study from New York State, 52 adult patients with erythema migrans who had not received treatment for Lyme disease underwent testing for Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and the deer tick virus subtype of Powassan virus.  Nearly 90% of the  patients showed no evidence of co-infection. Polymerase chain reaction (PCR) tests for B microti DNA were positive in 3 patients, one of whom also had a positive blood smear; these patients also had clinical signs suspicious for babesiosis. And additional 3 patients had elevated convalescent-phase IgG titers for B microti. [47]  

The possibility of co-infection with another tick-borne pathogen should be considered if the patient’s condition does not respond to treatment as expected with ordinary early Lyme disease. Evidence suggests that co-infected patients have more symptoms of longer duration compared with other patients. In addition, these patients may be sicker than others on first observation.

Results of some laboratory studies may suggest some of the other co-infecting tick-borne pathogens such as ehrlichial or babesial species. Most patients with ehrlichiosis have elevated levels of hepatic transaminases, leukopenia, and/or thrombocytopenia. In addition, some patients have morulae (intracytoplasmic inclusions) in white blood cells, as demonstrated on peripheral blood smears.

Patients with babesiosis often are anemic (hemolytic type) and may have thrombocytopenia. Blood smears reveal the malarialike intraerythrocytic parasite in this disease as well, as shown below.

Blood smear showing likely babesiosis. Babesiosis Blood smear showing likely babesiosis. Babesiosis can be difficult to distinguish from malaria on a blood smear.

Differential Diagnoses