Case Presentation: A 49 year-old man with a recent diagnosis of myasthenia gravis presented with 3 days of fever up to 103, rhinorrhea, frontal headache, mild lower extremity weakness, a mildly productive cough, and a leukocytosis to 16. As he had been started on prednisone and azathioprine 10 days prior to his presentation, he underwent a broad infectious work-up including chest x-ray, chest CT, lumbar puncture, urine, sputum, and blood cultures and respiratory viral panel. He was started on broad spectrum antimicrobials for concern for sepsis. He was also noted to have elevated liver function tests, and his azathioprine was held for this per neurology.Over the next 2 days the patient improved significantly with resolution of his fevers and lower extremity weakness and improvement in his liver function tests. His infectious work-up was negative apart from rhinovirus DNA found on the respiratory virus panel. His antibiotics were narrowed to piperacillin/tazobactam only, and neurology recommended restarting his azathioprine.
A few hours following the reinitiation of azathioprine the patient developed fever to 102, hypotension, joint pain, and a blanchable erythematous rash on his lower extremities. On laboratory evaluation the patient was seen to have worsening leukocytosis, a lactic acidosis, worsening liver function tests, and an acute kidney injury with white cells in the urine consistent with a nephritis. Blood, urine, and sputum cultures were again seen to be negative. Upon review of the literature the patient’s septic shock like symptoms were felt due to azathioprine hypersensitivity. After holding the azathioprine and stopping his antibiotics, his symptoms and laboratory abnormalities all resolved, and he was discharged home.

Discussion: Azathioprine hypersensitivity is a rare but serious drug reaction with onset typically occurring in the first few weeks after initiation of therapy. The most common symptoms are fever and hypotension. Other common symptoms are rashes, gastrointestinal symptoms, arthralgias, myalgias, and proximal muscle weakness. Laboratory abnormalities include evidence of hepatitis and nephritis with associated kidney injury. Skin of biopsy of the associated rash most often shows a neutrophilic dermatosis. Symptoms typically recur suddenly and with greater severity on rechallenge with azathioprine. Symptoms and lab abnormalities resolve with withdrawal of the drug. The mechanism of action is uncertain but is hypothesized to be due to a cytokine reaction as it does not appear to be IgE mediated or related to thiopurine methyltransferase (TMPT) levels.

Conclusions: It is important for hospitalists to be aware of azathioprine hypersensitivity reactions because their presentation commonly mimics sepsis, the symptoms can be severe, and the only treatment is withholding the azathioprine. With ever more patients on immunomodulating medications and the continued focus on the rapid treatment of sepsis, it is important for hospitalists to be cognizant of sepsis mimicking processes, so they can recognize them and take appropriate action.