SIROLIMUS-ASSOCIATED PULMONARY TOXICITY

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Abstract

Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

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Bronchiolitis obliterans organizing pneumonia.

T McLoud, G Epler, E A Gaensler … (1985)

In 50 of 94 patients with bronchiolitis obliterans we found no apparent cause or associated disease, and the bronchiolitis obliterans occurred with patchy organizing pneumonia. Histologic characteristics included polypoid masses of granulation tissue in lumens of small airways, alveolar ducts, and some alveoli. The fibrosis was uniform in age, suggesting that all repair had begun at the same time. The distribution was patchy, with preservation of background architecture. Clinically, there was cough or flu-like illness for 4 to 10 weeks, and crackles were heard in the lungs of 68 per cent of the patients. Radiographs showed an unusual pattern of patchy densities with a "ground glass" appearance in 81 per cent. Physiologically, there was restriction in 72 per cent of the patients, and 86 per cent had impaired diffusing capacity. Obstruction was limited to smokers. The mean follow-up period was four years. With corticosteroids, there was complete clinical and physiologic recovery in 65 per cent of the subjects; two died from progressive disease. This disorder differs from bronchiolitis obliterans with irreversible obstruction. It was confused most often with idiopathic pulmonary fibrosis. In view of the benign course and therapeutic response, a histologic distinction is important.

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A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts.

Graeme Macdonald, (2001)

Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.