This patient most likely has coinfection with Anaplasma phagocytophilum, a bacterium spread by the Ixodes tick (the same vector associated with Lyme disease). The constellation of fever, leukopenia, thrombocytopenia, and mild elevation in liver enzymes in a patient with recent Lyme disease is highly suggestive of anaplasmosis. Among patients with erythema migrans, up to 10% are coinfected with anaplasmosis. Although amoxicillin is active against Lyme disease, it is not effective therapy for A. phagocytophila. Doxycycline would have offered the advantage of treating the Lyme disease and an incubating asymptomatic infection with Anaplasma. Recrudescent symptoms of Lyme disease would not be expected in a patient receiving treatment, and patients with erythema migrans rarely develop later-stage disease after completing therapy.

Babesia microti is a parasite also transmitted by the Ixodes tick. Patients with symptomatic babesiosis often present with fever and signs of hemolysis, including jaundice, scleral icterus, and splenomegaly. This patient has leukopenia, thrombocytopenia, and a normal hematocrit and haptoglobin level, making babesiosis unlikely.

Powassan virus is also spread by Ixodes ticks but causes meningoencephalitis. No human coinfection has been documented with both Lyme disease and Powassan virus infection.

Serial episodes of erythema migrans can occur, and, until recently, it has been debated whether a second episode of erythema migrans represents relapse of inadequately treated disease. Genotyping of sequential erythema migrans lesions has shown that these cases are caused by a genetically distinct strain of Borrelia and represent reinfection rather than latent infection.