Correspondence
Interstitial Pneumonitis Associated with Sirolimus Therapy in Renal-Transplant Recipients
N Engl J Med 2000; 343:1815-1816December 14, 2000
- Article
To the Editor:
Morelon et al. (July 20 issue)1 described three patients in whom interstitial pneumonitis was thought to be related to sirolimus therapy, because it occurred during therapy and resolved after sirolimus was discontinued and because other causes were absent.
To date, the Food and Drug Administration (FDA) has received reports of 34 cases of interstitial pneumonitis that were temporally associated with sirolimus therapy (including the 3 described by Morelon et al.). All but two case reports2 were from clinical studies of sirolimus. Thirty-two patients were being treated with sirolimus after receiving kidney transplants, one after receiving a liver transplant, and one after receiving a heart transplant. The patients ranged in age from 23 to 69 years; 13 were women and 21 were men. The pneumonitis occurred within 6 months after the initiation of sirolimus therapy in 16 patients, within 6 to 12 months in 6 patients, and after 12 months in 11 patients; the interval between the initiation of therapy and the onset of pneumonitis was unstated in one report. The lung disease was reported as pneumonitis or interstitial pneumonitis in 16 patients, as bronchiolitis obliterans with organizing pneumonia in 6 patients, as interstitial pneumonia in 6 patients, as interstitial pneumonopathy in 5 patients, and as pulmonary alveolar proteinosis in 1 patient. In seven patients, surgical biopsy confirmed the presence of interstitial pneumonitis. In 14 patients, common infectious causes of pneumonitis after transplantation were ruled out. The pneumonitis cleared after the discontinuation of sirolimus in eight patients; in four of the eight patients, other drugs that had been considered as more likely causes had first been discontinued, with no improvement. Four patients died, one apparently as a result of pneumonitis (from respiratory failure).
The patients described by Morelon et al. were extensively evaluated with radiographic, physiological, and invasive testing. Few of the other reports received by the FDA included such information, but many had the results of one or more such tests, and in most cases the results were consistent with those of Morelon et al. In addition, six patients had new-onset anemia, suggesting possible alveolar hemorrhage (and two of the six patients had evidence of hemorrhage on examination of bronchoalveolar-lavage fluid).
We agree with Morelon et al. that sirolimus therapy should be considered in the differential diagnosis of interstitial pneumonitis in patients who are taking the drug.
(This letter contains the professional views of the authors and does not necessarily represent the official position of the FDA.)
2 ReferencesSarah J. Singer, R.Ph.
Rosemary Tiernan, M.D.
Eugene J. Sullivan, M.D.
Food and Drug Administration, Rockville, MD 208571
Morelon E ,Stern M ,Kreis H . Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med 2000;343:225-226
Full Text | Web of Science | Medline2
Mahalati K ,Murphy DM ,West ML . Bronchiolitis obliterans and organizing pneumonia in renal transplant recipients. Transplantation 2000;69:1531-1532
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: Singer et al. report 34 cases of interstitial pneumonitis in recipients of renal, liver, or heart transplants who were taking sirolimus. The clinical presentation of these patients was similar to that of our patients and those described elsewhere.1
The diagnosis of sirolimus-induced pneumonitis is not an easy one. The diagnostic criteria should include the occurrence of improvement after the discontinuation of the drug; this was reported in only 8 of the 34 patients. In the absence of information about the effects of the discontinuation of sirolimus in most of the patients, it may be premature to attribute their pneumonitis to sirolimus. We think that extensive studies to rule out infectious pneumonitis should be performed before pneumonitis can be attributed to sirolimus.
Sirolimus-related pneumonitis may be dose-dependent. In fact, our three patients had high trough plasma sirolimus concentrations. In addition, one of the patients described by Mahalati et al.,1 as well as another patient recently seen by our group, recovered completely after the dose of sirolimus was reduced.
Given the growing role of sirolimus in immunosuppressive therapy, every new case of interstitial pneumonitis in patients who are taking sirolimus should be analyzed in order to delineate the effects of this drug.
1 ReferencesEmmanuel Morelon, M.D., Ph.D.
Hôpital Necker, 75743 Paris CEDEX 15, FranceMarc Stern, M.D.
Hôpital Foch, 92150 Suresnes, FranceHenri Kreis, M.D.
Hôpital Necker, 75743 Paris CEDEX 15, France1
Mahalati K ,Murphy DM ,West ML . Bronchiolitis obliterans and organizing pneumonia in renal transplantation recipients. Transplantation 2000;69:1531-1532
CrossRef | Web of Science
- Citing Articles (33)
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H.S. Lee, K.H. Huh, Y.S. Kim, M.S. Kim, H.J. Kim, S.I. Kim, D.J. Joo. (2012) Sirolimus-Induced Pneumonitis After Renal Transplantation: A Single-Center Experience. Transplantation Proceedings 44:1, 161-163
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L. Bertolini, A. Vaglio, L. Bignardi, C. Buzio, M. De Filippo, A. Palmisano, K. Mercati, M. Zompatori, U. Maggiore. (2011) Subclinical Interstitial Lung Abnormalities in Stable Renal Allograft Recipients in the Era of Modern Immunosuppression. Transplantation Proceedings 43:7, 2617-2623
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Elaine Long, Kathryn J. Wood. (2009) Regulatory T Cells in Transplantation: Transferring Mouse Studies to the Clinic. Transplantation 88:9, 1050-1056
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Jaime Villanueva, Ali Boukhamseen, Sangeeta M. Bhorade. (2005) Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. The Journal of Heart and Lung Transplantation 24:4, 421-425
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