A 47-year-old man with no significant medical history presented with a 5-day history of an expanding plaque on his left thigh. The patient had fevers up to 38.1°C, chills, malaise, and joint stiffness. He noted recent time spent in the woods but denied known tick bites. On examination, the left thigh had a nontender, oval plaque with central vesicles on a red base and a surrounding rim of pink erythema (Figure 1). Based on the patient's clinical history and examination, a diagnosis of vesicular erythema migrans (EM) was made and doxycycline was initiated. Two days after antibiotic initiation, the patient presented to the emergency department with ill-defined, rapidly spreading, painless erythema contiguous with the original plaque. The patient's temperatures fluctuated between 35.6°C to 40°C. Given the concern for cellulitis, the patient was admitted to rule out infectious causes and was transitioned to empiric broad-spectrum antibiotics. Laboratory studies were notable for a normal complete blood cell count, elevated levels of C-reactive protein (100.45 mg/L; reference range 0–10 mg/L), Lyme total antibodies elevated to 4.8, and Lyme 23-kD immunoglobulin M reactive. Point of care ultrasound revealed cobblestoning with no discrete fluid collection, concerning for possible cellulitis. Within 24 h of presentation, the patient's symptoms improved with receding erythema and temperature stabilization without antipyretics. The patient was diagnosed with Jarisch–Herxheimer reaction (JHR) and continued on a 21-day course of oral cefuroxime with complete resolution of all symptoms.

Figure 1Clinical progression of vesicular erythema migrans with Jarisch–Herxheimer Reaction. (A) Large, nontender, oval, dark red plaque with central vesiculation on the left thigh consistent with vesicular erythema migrans. (B) Spreading erythema in the setting of Jarisch–Herxheimer reaction 48 h after initiation of doxycycline. (C) Receding erythema with resolution of Jarisch–Herxheimer reaction 24 h after presentation to the hospital. (D) Near complete resolution of erythema migrans after 7 days of ongoing antibiotic therapy.