Sirolimus‐associated interstitial pneumonitis in solid organ transplant recipients

Abstract

Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.

A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer

“…19 The frequency and severity of biochemical abnormalities and nausea, stomatitis, rash, diarrhea, anorexia, and vomiting were consistent with the results of other studies of everolimus monotherapy 12,15 and other mTOR inhibitors, [20][21][22] although the frequency of pneumonitis, both overall and grade 3, was found to be greater than previously reported. Pneumonitis is known to develop in patients treated with mTOR inhibitors in the transplantation setting [23][24][25][26] and has been reported in other studies in cancer patients treated with everolimus 27 and temsirolimus. 28 Among 34 women with metastatic breast cancer who were treated with everolimus on either a daily (10 mg/day) or weekly (70 mg/week) schedule, El-Maraghi et al 27 reported clinical and/or radiologic changes that were consistent with possible interstitial lung disease (ILD) in 15 patients, 4 of whom had grade 2 or 3 changes; 5 patients discontinued therapy because of ILD, and all patients with grade 2 of 3 toxicities were managed successfully with glucocorticoids.…”

The use of everolimus in renal-transplant patients

“…35 These differences may explain certain variations in the safety profiles of the two agents. For example, sirolimus has been associated with the development of pneumonitis following renal transplantation, [56][57][58] which may be a cause of pulmonary fibrosis in later stages of the disease. By contrast, no cases of pneumonitis have been reported in renal-transplant patients receiving everolimus with low-dose CsA.…”

Fatal diffuse alveolar hemorrhage associated with sirolimus after allogeneic hematopoietic cell transplantation

“…[5][6][7][8] Usually it is reversible, with a 4.8% mortality rate. 8 High SRL levels (415 ng/dl), late drug exposure (that is, switch in therapy) and male gender are the risk factors. 8 The mechanism of SRLassociated pulmonary toxicity is not well understood.…”

“…8 High SRL levels (415 ng/dl), late drug exposure (that is, switch in therapy) and male gender are the risk factors. 8 The mechanism of SRLassociated pulmonary toxicity is not well understood. Etiologies include dose-dependent or immune-mediated toxicity, and direct drug toxicity.…”

“…Etiologies include dose-dependent or immune-mediated toxicity, and direct drug toxicity. [8][9][10] Four diagnostic criteria have been proposed by Morelon et al 9 for the diagnosis of SRL-associated lung toxicity: (1) SRL exposure before the onset of pulmonary symptoms; (2) exclusion of infection and other possible causal agents; (3) resolution of symptoms and radiological findings within 3 months after discontinuing or reducing SRL doses; and (4) lymphocytotoxic alveolar cell profile and pathological findings.…”