Methotrexate-induced sudden fatal pulmonary reaction

A teenage girl in bone marrow remission with acute lymphocytic leukemia died suddenly from pulmonary edema. She had taken her first oral dose of methotrexate and cyclophosphamide 10 hours previously when she was feeling well and was asymptomatic. One week previously she had received the last of four intrathecal injections of methotrexate. Autopsy showed marked pulmonary edema as well as chronic lung changes, as previously described in patients with methotrexate pneumonitis. There is usually at least a 12-day interval from the onset of administration of methotrexate to the onset of the lung toxicity. The authors suggest the patient was sensitized by the intrathecal methotrexate and then reacted with angioneurotic edema of the lung when given the first oral dose of methotrexate. Careful examination for infectious agents, including electron microscopy, was negative.