Sirolimus-Induced Interstitial Pneumonitis After Renal Transplantation (2004)

Sirolimus is a new immunosuppressive drug with increasing use in organ transplantation. We report a case of sirolimus-associated interstitial pneumonitis and review the evidence of such cases up to date. A 51-year-old female, ten years after renal transplantation, presented to our ward complaining of vomiting and abdominal pain. The complaints were attributed to gastroenteritis and resolved shortly after her arrival. Routine chest x-ray revealed bilateral infiltrates (compared with a normal chest x-ray 10 months prior to her admission). Her regular drug treatment included prednisone, FK506, losartan, simvastatin, famotidine, furosemide and metoprolol. She had been started on sirolimus eleven months prior to hospitalization. She denied dyspnea, but on exam was found to be tachypneic and hypoxic (room air saturation 95%), with bilateral dry crackles on lung auscultation. Differential diagnosis included opportunistic infections vs. interstitial pneumonitis due to sirolimus treatment. Broad-spectrum empirical antibiotic coverage was initiated. Specific staining, serology, blood cultures, urine, and bronchoalveolar lavage (BAL) ruled out pulmonary infections (specifically cytomegalovirus, legionella, nocardia, cryptococcus, tuberculosis, adenovirus and pneumocystic carinii). BAL predominantly showed macrophages, particularly siderophages. Transbronchial biopsy showed features suggestive of chronic interstitial pneumonitis, with no evidence of tumor cells, granulomas, or infectious disease. Sirolimus was presumed to be the cause of interstitial pneumonitis and was thus discontinued, as was the antibiotic treatment. Follow up within 6 weeks found the patient well, with no respiratory complaints or findings on physical exam. Chest x-ray showed near total resolution of previous pulmonary infiltrates. Morleon et al. (1) have published a series of eight renal transplant recipients who developed unexplained interstitial pneumonitis associated with sirolimus use. They conclude that interstitial pneumonitis due to sirolimus is probable when it occurs during sirolimus therapy, other probable causes have been ruled out, and resolution has occurred within three months of discontinuation of the drug or dose reduction. Lymphocytic predominance in BAL was suggestive, but not offered as a criterion. In fact, authors state that presence of siderophages, neutrophils, and CD8 lymphocytes suggests the injury may not be pure hypersensitive pneumonitis in all cases. In addition to this series, two other sirolimus-induced interstitial pneumonitis cases have been described (2,3), while additional patients were reported to have bronchiolitis obliterans or pulmonary alveolar proteinosis. Singer et al. (4), from the Food and Drug Administration (FDA), recount 34 cases of sirolimus-associated lung disease reported to the FDA up to the year 2000, though most do not answer the above criteria (not all cases were defined as pneumonitis, sirolimus was discontinued in only eight patients, and other infectious causes were ruled out in only 14 patients). Physicians should be familiar with sirolimus-induced interstitial pneumonitis as an important differential diagnosis for pulmonary opportunistic infections in transplanted patients. The various patterns described so far suggest we have yet to define the precise mechanism(s) involved. It is vital to continue informing cases of suspected sirolimus-associated interstitial pneumonitis, in order to better recognize the nature and magnitude of this side effect. Daphna Shefet Itsik Ben-Dor Department of Internal Medicine Rabin Medical Center Petach Tikvah, Israel Shamir Lustig Department of Nephrology Rabin Medical Center Petach Tikvah, Israel