(Chest. 2004;126:642-644.)
© 2004
American College of Chest Physicians
Pulmonary Sarcoidosis Following Stem Cell Transplantation*
Is It More Than a Chance Occurrence?
Rajesh Bhagat, MD, FCCP;
David A. Rizzieri, MD;
James J. Vredenburgh, MD;
Nelson J. Chao, MD and
Rodney J. Folz, MD, PhD
* From the Division of Pulmonary, Allergy, and Critical Care Medicine (Drs. Bhagat and Folz); Duke University Adult Bone Marrow Transplant and Stem Cell Transplant Program (Drs. Rizzieri, Vredenburgh, and Chao), Duke University Medical Center, Durham, NC.
Correspondence to: Rodney J. Folz, MD, PhD, Duke University Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, Box 2620, Room 331 MSRB, Durham, NC 27710; e-mail: rodney.folz{at}duke.edu
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Abstract
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Noninfectious pulmonary complications are one of the major side effects of hematopoetic stem cell transplant (HSCT); however, the development of pulmonary sarcoidosis post-HSCT is uncommon, with only three cases previously reported. In each of those cases, sarcoidosis was also diagnosed in the stem cell donor. We now report four cases of de novo pulmonary sarcoidosis occurring post-HSCT (3 autologous HSCT and 1 allogeneic HSCT). We suggest that pulmonary sarcoidosis may develop following either autologous or allogeneic HSCT, and the prevalence may be 10-fold higher than that of the normal population.
Key Words: bone marrow transplant • granuloma • sarcoid • stem cell transplant
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Introduction
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Hematopoetic stem cell transplantation (HSCT) is being used increasingly for the management of malignant and nonmalignant conditions. Pulmonary complications can be seen in 10 to 64% of patients undergoing HSCT, with the incidence seemingly dependent on the specific therapeutic regimen used.1 In over half these patients, noninfectious pulmonary complications are responsible for significant morbidity and mortality. Noninfectious pneumonitis may present as idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, or delayed pulmonary toxicity syndrome, as well as other drug toxicity related reactions.1 The development of sarcoidosis post-HSCT is very uncommon, with only three reports suggesting the possible transmission of sarcoidosis from the donor stem cells to the allogeneic HSCT recipient.234 The paucity of literature on the association of sarcoidosis with HSCT prompted this report.
Here, we present four patients who developed biopsy-proven pulmonary nonnecrotizing epithelioid granuloma-like lesions compatible with sarcoidosis following HSCT. Three of the patients were treated for breast cancer with high-dose chemotherapy along with autologous hematopoetic stem cell transplantation (autoHSCT), while the fourth patient received an allogeneic HSCT (alloHSCT) for chronic myeloid leukemia.
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Case Reports
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Case 1
A 51-year-old woman was diagnosed with chronic myeloid leukemia with a positive Philadelphia chromosome. She was treated with hydroxyurea for 6 months and subsequently was maintained on interferon therapy. Her disease relapsed, and she underwent high-dose cyclophosphamide therapy and total body irradiation, followed by alloHSCT. Post-HSCT, her course was complicated by diffuse alveolar hemorrhage, influenza A pneumonia, and acute graft-vs-host disease requiring high dose steroids and cyclosporin. Six months following HSCT, she developed shortness of breath for a period of 2 weeks and low-grade fever. A chest CT scan showed bilateral ground glass and nodular opacities. Transbronchial biopsies showed nonnecrotizing granulomas consistent with sarcoidosis. She was treated with oral prednisone (40 mg/d for 8 weeks and gradually tapered over the next 4 months) with resolution of both her symptoms and abnormal radiographs.
Case 2
Following 6 months treatment with autoHSCT for recurrent breast cancer, a 50-year-old woman was referred to us for evaluation of miliary lesions seen on chest roentgenogram. The patient gave a history of vague joint pains, fatigue, lethargy, and low-grade fever for the past one month. A CT scan of the chest revealed bilateral hilar lymphadenopathy and diffuse miliary opacities. Transbronchial biopsies revealed nonnecrotizing epithelioid granuloma consistent with sarcoidosis. Flow cytometry of BAL fluid revealed a predominantly polyclonal B-cell lymphocytic population. The patient was treated with oral prednisone (40 mg/d), with symptomatic improvement, normalization of her pulmonary function tests within 8 weeks, and resolution of her miliary opacities. However, the hilar lymphadenopathy persisted.
Case 3
A 47-year-old woman 12 weeks following autoHSCT for advanced-stage breast cancer was referred for evaluation of new hilar and mediastinal lymphadenopathy, with pulmonary nodules noted on chest CT. Transbronchial biopsies revealed nonnecrotizing granuloma consistent with sarcoidosis. She was treated with oral prednisone (60 mg/d), and her intrathoracic lesions resolved completely after 8 weeks. Six months later, when the prednisone was tapered to below 10 mg/d, she developed skin lesions, which on biopsy were consistent with sarcoidosis. A chest x-ray revealed an increase in parenchymal opacities necessitating an increase in steroids.
Case 4
A 48-year-old woman had undergone autoHSCT for recurrent breast cancer and 10 years later was found to have new onset mediastinal adenopathy. Mediastinoscopy showed no evidence for tumor but did find nonnecrotizing granulomas consistent with sarcoidosis. Because she was asymptomatic, no treatment was given, and a 1-year radiographic follow-up was unchanged.
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Discussion
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Nonnectrotizing granulomas have been associated with infections, inflammatory conditions, and/or drugs, but rarely have they been reported following HSCT.5 All four of our patients had no evidence for infections (mycobacterium and fungus) based on surgical pathology stains and cultures. A review of the literature has revealed three case reports of patients developing sarcoidosis following alloHSCT.234 However, these patients received stem cells from siblings who were each diagnosed with pulmonary sarcoid, suggesting the possibility of a transmissible agent.234
There are two major hypotheses concerning the pathogenesis of sarcoidosis. First, sarcoidosis is due to one or more environmental inhalational triggers. Second, sarcoidosis is due to an abnormal immunological host response to common antigenic triggers. Either, or both, may induce the expression of monocytic-derived cytokines and chemokines, and/or enhance Th1-type responses,6 leading to the development of the prototypical microscopic finding in sarcoidosis, the epithelioid granuloma. We speculate that the postHSCT lung environment may promote nonnecrotizing epithelioid granulomatous formation caused by high levels of some of these chemokines including MCP-1, CCR1, CCR2, IL-8, and Rantes.78 Based on approximately 2,600 HSCTs performed over a 12-year period and 4 cases of sarcoid, we estimate the prevalence of sarcoidosis in the HSCT population to be about 150 cases per 100,000 or about 10-fold higher than that of the normal population.
Clinically, all cases of sarcoidosis had their onset of granulomatous response after complete engraftment of their bone marrow, indicating that a responsive immune system is a prerequisite for the formation of granuloma (Table 1
). In the setting of malignancy, the development of mediastinal and/or hilar lymphadenopathy raises concerns of relapsed neoplastic processes and can result in unnecessary distress and further aggressive chemotherapy. In fact, two of our patients were scheduled to receive chemotherapy for "metastatic disease" the week following their bronchoscopy, as they both had hypermetabolic activity on positron emission tomography studies.
In conclusion, pulmonary epithelioid granulomas suggestive of sarcoidosis can develop following HSCT and may be more common than previously thought. Therefore, in the appropriate clinical setting, lung tissue biopsies should be obtained to evaluate for this possibility. Further investigations into the underlying mechanisms of this association may also be helpful in our understanding of the pathogenesis of pulmonary sarcoidosis.
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Footnotes
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Abreviations: alloHSCT = allogeneic HSCT; autoHSCT = autologous HSCT; HSCT = hematopoetic stem cell transplant
This work is funded in part by National Institutes of Health, National Research Service Award HL-07538 to R.B. and Grant HL-55166 to R.J.F.
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References
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- Folz, RJ (1999) Mechanisms of lung injury following bone marrow transplantation. Am J Respir Cell Mol Biol 20,1097-1099[Free Full Text]
- Heyll, A, Meckenstock, G, Aul, C, et al Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14,161-164[ISI][Medline]
- Tauro, S, Mahendra, P Resolution of sarcoidosis after allogeneic bone marrow transplantation with donor lymphocyte infusions. Bone Marrow Transplant 2001;27,757-759[Medline]
- Sundar, KM, Carveth, HJ, Gosselin, MV, et al Granulomatous pneumonitis following bone marrow transplantation. Bone Marrow Transplant 2001;28,627-630[Medline]
- Foucer, K Differential diagnosis of lymphoid infiltrate in bone marrow. Foucer, K eds. Bone marrow pathology 2001,526 ASCP Press. Chicago, IL:
- Conron, M, Du Bois, RM Immunological mechanisms in sarcoidosis. Clin Exp Allergy 2001;31,543-554[CrossRef][Medline]
- Bhalla, KS, Folz, RJ Idiopathic pneumonia syndrome following syngeneic bone marrow transplant in mice. Am J Respir Crit Care Med 2002;166,1579-1589[Abstract/Free Full Text]
- Panoskaltsis-Mortari, A, Strieter, RM, Hermanson, JR, et al Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation. Blood 2000;96,834-839[Abstract/Free Full Text]
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Abstract
Introduction
