Several cases of pneumocystosis developing after lowering cortisol serum level have been reported, mostly in patients with ectopic Cushings syndrome. We report here 2 cases of pneumocystosis which developed after initiation of treatment with metyrapone, one in a patient with Cushings disease, and the second in a patient with ectopic ACTH secretion by a prostate endocrine carcinoma. Both cases presented severe Cushings syndrome. We then analyzed the periodic safety update report (PSUR) on metyrapone from 02/2012 to 06/2018 and the litterature Patient 1, a 39 year-old-woman, was diagnosed with severe Cushings disease and metyrapone treatment was started to improve her condition before pituitary surgery. She developed respiratory symptoms 4 days after starting treatment. Patient 2, a 82 year-old-man, was diagnosed for an ectopic Cushings syndrome due to endocrine prostate cancer, with diffuse bones metastasis. Respiratory failure occurred 30 days after metyrapone treatment initiation. In both cases, chest CT scan performed after development of dyspnea showed lesional pulmonary oedema and Broncho alveolar lavage (BAL) allowed identification of Pneumocystis jirovecii by PCR (in patient 2, co infection with CMV). Both patients were treated by trimethoprim-sulfametoxazole. Patient 1 was cured, but patient 2 died several days later from severe sepsis with multivisceral failure. Analysis of PSUR identified 5 cases of pneumocystosis, none of which were letal. Analysis of the literature identified 12 cases of pneumocystis jirovecii pneumonia linked to metyrapone in patients with very high levels of cortisol and other cases revealing several days after lowering cortisol levels either with ketoconazole, etomidate bromide or mifepristone. Physiopathology remains unclear but the hypothesis of immune reconstitution inflammatory syndrome is compelling: on the one hand, severe hypercorticism leads to an immunodepression state which favors the colonization by opportunistic organisms, and on the other hand it decreases inflammatory response, which delays apparition of symptoms. After lowering cortisol level, recovery of immunity might trigger an inappropriate host inflammatory response as part of a cytokine storm, which would make clinical features appear. These case reports should draw attention to the risk for a potentially letal pulmonary infection that may reveal only after initiation of medical therapy aimed at lowering cortisol levels, in patients with severe Cushings syndrome who do not show any pulmonary symptoms initially. This risk might justify systematic prophylactic treatment with trimethoprim-sulfametoxazole in such patients, a treatment which is so far not clearly recommanded in the current guidelines.
18 - 21 May 2019
European Society of Endocrinology