Noncardiogenic pulmonary edema following injection of methotrexate into the cerebrospinal fluid

Abstract

The most common pulmonary disorder induced by methotrexate is a gradually developing interstitial pneumonitis. The associated clinical manifestations include slowly progressive dyspnea and nonproductive cough, with extensive radiographic changes. One case has been reported following intrathecal methotrexate administration; the remainder occurred after either intravenous or oral therapy. We report two cases of rapidly developing respiratory distress following the administration of methotrexate into the cerebrospinal fluid. The clinical courses, radiologic findings, and, in one patient, the pathologic nature, are consistent with noncardiogenic pulmonary edema.

Noncardiogenic Pulmonary Edema in Low-dose Oral Methotrexate Therapy

“…Noncardiogenic pulmonary edema (NCPE), a syndrome characterized by severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of congestive heart failure, is reported as a rare complication of MTX therapy in high doses for cancer patients (6)(7)(8)(9)(10). Given that the initial differentiation between the types of MTX pneumonitis is difficult, the diagnosis of drug-induced NCPE would be an exercise of exclusion, and in most of the past reports on MTX-induced pulmonary edema, the diagnoses were made using the clinical course, radiologic findings, and in some, pathological findings (6)(7)(8)(9).…”

“…Given that the initial differentiation between the types of MTX pneumonitis is difficult, the diagnosis of drug-induced NCPE would be an exercise of exclusion, and in most of the past reports on MTX-induced pulmonary edema, the diagnoses were made using the clinical course, radiologic findings, and in some, pathological findings (6)(7)(8)(9). Most of these reports of pulmonary edema caused by MTX involved intrathecally administered MTX, and although the mechanism is still unknown, neurogenic pulmonary edema has been speculated as the cause for these past cases.…”

“…Acute interstitial pneumonitis is the most common, followed by interstitial fibrosis; whereas the latter three conditions are quite rare. All pulmonary conditions have been reported in low-dose MTX therapy for RA, except for noncardiogenic pulmonary edema, which has only been seen in patients receiving high-dose MTX for the treatment of malignancies (6)(7)(8)(9).…”

Pulmonary Toxicity of Cytotoxic and Immunosuppressive Agents: A Review

“…Enteric protein loss, caused by the toxic action of cytosine arabinoside, results in hypoproteinemia which is causally related to the appearence of non-cardiogenic pulmonary oedema (30). Intrathecal administration of methotrexate may cause pulmonary oedema, possibly of neurogenic origin (31). Mitomycin-induced haemolytic-uremic syndrome occasionally produces alveolar haemorrhagic oedema (32)(33)(34)(35).…”

“…The incidence of cytosine arabinoside-induced pulmonary oedema is clearly linked to dose, and reaches about 20% in high-dose schedules (124). Only five cases of pulmonary oedema are reported following methotrexate therapy, and all of them received methotrexate intrathecally (31,81,82,118).…”