Ann Thorac Surg 2009;87:e6-e7. doi:10.1016/j.athoracsur.2008.07.107
© 2009 The Society of Thoracic Surgeons
Case Reports
Sirolimus Treatment for Recurrent Lymphangioleiomyomatosis After Lung Transplantation
Fengshi Chen, MD,
Mitsugu Omasa, MD,
Nobuyuki Kondo, MD,
Takuji Fujinaga, MD,
Tsuyoshi Shoji, MD,
Hiroaki Sakai, MD,
Toru Bando, MD*
Department of Thoracic Surgery, Kyoto University, Sakyo-ku, Kyoto, Japan
Accepted for publication July 29, 2008.
* Address correspondence to Dr Bando, Department of Thoracic Surgery, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan (Email: bando{at}kuhp.kyoto-u.ac.jp).
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Abstract
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Pulmonary lymphangioleiomyomatosis is a rare disease that generally progresses to respiratory failure. We experienced a patient who had recurring lymphangioleiomyomatosis in the transplanted lungs. A chest computed tomographic scan showed a progressing emphysematous change. The patient had a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis. We treated the patient with sirolimus for three years. Chest computed tomography showed no sign of exacerbation during the late 3 years, whereas pulmonary function test revealed a slight increase after the use of sirolimus. Bronchial stricture also disappeared almost completely. This is the first reported case with sirolimus treatment for post-transplant recurrent lymphangioleiomyomatosis.
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Introduction
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We reported a case of recurrent pulmonary lymphangioleiomyomatosis (LAM) after lung transplantation [1]. After the diagnosis, we treated the patient with sirolimus successfully for 3 years, and therefore we decided to report this case again here. The LAM is a rare disease characterized by abnormal proliferation of smooth-muscle cells within the lung, resulting in respiratory failure. Although significant progress has been made in the molecular biology of LAM, there is still no established evidence on how these patients should be treated. Recently, loss-of-function mutations in the tumor suppressor genes tuberous sclerosis 1 and 2 have been described in LAM [2]. The use of sirolimus to correct the cellular abnormality produced by loss of function of tuberous sclerosis 1 and 2 is an exciting development.
A 23-year-old woman with pulmonary and abdominopelvic LAM undertook living-donor lobar lung transplantation in June 2003. The donors were her mother for the right lower lobe and her sister for the left lower lobe. Both donors do not have any findings suggesting that they also suffer from LAM. She was discharged home and enjoyed her life without limitations. Maintenance immunosuppression included tacrolimus, azathioprine, and prednisone. One year after lung transplantation, she felt a sudden left chest pain and had a cough with chylous sputum. A chest computed tomographic (CT) scan showed increased pleural effusion on the right side and left pneumothorax and infiltrates at the bottom of the left lung. After follow-up in the hospital, the pneumothorax diminished gradually. The infiltrates also completely disappeared soon after discharge. The same events recurred an additional two times in 4 months and every time she recovered. Since then, she repeatedly complained of feeling that a small pneumothorax had occurred and then resolved quickly. During this period, her pulmonary function test results remained stable. However, her chest CT scan revealed emphysematous change of the subpleural region in both lungs. Three months later a follow-up CT scan showed that emphysematous change of the subpleural region was significantly exacerbated. Transbronchial lung biopsy finally proved a recurrent LAM in the transplanted lungs (Fig 1). She also showed a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis (Fig 2A). After repetitious informed consents, sirolimus (rapamycin) treatment was started in August 2005. Azathioprine was replaced with sirolimus. Tacrolimus and sirolimus were aimed to keep the trough level of drug concentrations at 4 to 8 µg/mL and 5 to 8 µg/mL, respectively. At first, 1 mg of rapamycin was given daily, and later 1 mg had been given daily or every other day to maintain the appropriate serum level for 3 years. After the sirolimus therapy, her complaint of a feeling that something was wrong in her chest significantly decreased in frequency. Furthermore, a chest CT scan showed no sign of exacerbation during the late 3 years, whereas a pulmonary function test revealed a slight increase after the use of sirolimus (Fig 3). Bronchoscopic findings and follow-up chest CT scan also showed the previously seen stricture disappeared almost completely (Fig 2B). Now she is very well without any sirolimus-related side effects.
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Fig 1. Pathologic findings of the specimen taken by transbronchial lung biopsy showed a typical lymphangioleiomyomatosis lesion. The smooth muscle cells showed a strong reaction with monoclonal antibody Human Melanoma Black 45 (Human Melanoma Black 45 stain; original magnification x40).
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Fig 2. (A) Chest computed tomographic (CT) scan showed a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis (arrow). (B) Follow-up chest CT scan approximately 2 years after sirolimus treatment showed the previously seen stricture disappeared almost completely (arrow).
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Fig 3. Follow-up pulmonary function test after lung transplantation. (FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity.
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Comment
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Sirolimus is a specific ribosomal protein S6 kinase-1 inhibitor and abolishes LAM cell abnormal proliferation in vitro [3]. Thus, sirolimus is highly expected as one of the promising drugs for LAM [4]. Taille and colleagues [5] first reported an experience of sirolimus for a pre-transplant LAM patient. The initial trial of sirolimus assessing its safety and efficacy in LAM and tuberous sclerosis-related angiomyolipoma will be reported soon, and the next trial will also be waiting for registration. In our patient, we set the trough level of sirolimus as well as tacrolimus, according to several reports. To avoid adverse side effects, such as pulmonary toxicity, we decreased the level of sirolimus to less compared with a report by Villanueva and colleagues [6].
In our patient, we believe we could stop the deterioration of the disease progression to some extent. We could not explain the improvement of the bronchial stricture, but one of the possible reasons is that sirolimus therapy reduced the chronic stimulation, such as cough with chylous sputum. This case supports the hypothesis that given its antiproliferative effects on smooth-muscle cells, sirolimus could be a therapeutic option for LAM.
We believe that this is the first report of sirolimus treatment for the recurrence of LAM after lung transplantation. To date, there have been no reported cases of LAM patients who received a second transplant as a result of recurrence in the pulmonary allograft [7]. Therefore, the clinical significance of LAM recurrence remains unclear and the accumulation of recurrent cases is needed.
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References
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- Chen F, Bando T, Fukuse T, et al. Recurrent lymphangioleiomyomatosis after living-donor lobar lung transplantation Transplant Proc 2006;38:3151-3153.[Medline]
- Strizheva GD, Carsillo T, Kruger WD, et al. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis Am J Respir Crit Care Med 2001;163:253-258.[Abstract/Free Full Text]
- Goncharova EA, Goncharov DA, Spaits M, et al. Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: role for tumor suppressor TSC2 Am J Respir Cell Mol Biol 2006;34:561-572.[Abstract/Free Full Text]
- Moses MA, Harper J, Folkman J. Doxycycline treatment for lymphangioleiomyomatosis with urinary monitoring for MMPs N Eng J Med 2006;354:2621-2622.[Medline]
- Taille C, Debray MP, Crestani B. Sirolimus treatment for pulmonary lymphangioleiomyomatosis Ann Int Med 2007;146:687-688.[Medline]
- Villanueva J, Boukhamseen A, Bhorade SM. Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus J Heart Lung Transplant 2005;24:421-425.[Medline]
- Kpodonu J, Massad MG, Chaer RA, et al. The US experience with lung transplantation for pulmonary lymphangioleiomyomatosis J Heart Lung Transplant 2005;24:1247-1253.[Medline]
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April 20, 2011;
29(12):
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Abstract
Introduction
