Pediatr Transplantation 2015: 19: E75–E77
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12438
Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation Garrod AS, Goyal RK, Weiner DJ. (2015) Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation. Pediatr Transplant, 19: E75–E77. DOI: 10.1111/petr.12438. Abstract: Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported.
Andrea S. Garrod1, Rakesh K. Goyal2 and Daniel J. Weiner3 1
Division of Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA, 2Blood and Marrow Transplantation and Cellular Therapies, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA, 3Divisions of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics,Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Key words: pediatrics – hematopoietic stem cell transplantation – sirolimus – interstitial lung disease – lung function tests Daniel J. Weiner, MD, Division of Pulmonary Medicine, Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Tel.: +1 412 692 5630 Fax: +1 412 692 6645 E-mail: [email protected] Accepted for publication 9 January 2015
Sirolimus is an immunosuppressive medication used commonly for prophylaxis and treatment of graft-versus-host disease in SOT and allogeneic HCT patients (1). Side effects include thrombocytopenia, hyperlipidemia, and rarely pulmonary toxicity (2). The vast majority of the respiratory complications have been reported in adult SOT patients (3) and have never been reported in a pediatric HCT patient. When interstitial pneumonitis develops, patients present with symptoms including dyspnea, fatigue, fever, and rarely hemoptysis (3). Chest radiography and computed tomography scans are characterized by bilateral interstitial infiltrates. Bronchoalveolar lavage fluid typically indicates a lymphocytic alveolitis and rarely shows evidence of hemorrhage. Pulmonary function testing demonstrates a restrictive defect reflecting the interstitial findings (2).
Abbreviations: HCT, hematopoietic stem cell transplantation; ILD, interstitial lung disease; SOT, solid organ transplant.
Case history
An eight-yr-old boy with a history of acute lymphoblastic leukemia and subsequent myelodysplastic syndrome underwent allogeneic matched HCT. His post-transplantation course was complicated by severe acute and chronic graft-versushost disease of the skin and gut which was treated with sirolimus. Two yr after transplant, he was noted to have nocturnal hypoxemia and polycythemia while hospitalized for Clostridium difficile colitis. He reported dyspnea and dry cough with exercise, and examination was notable for digital clubbing. A bronchoalveolar lavage was performed which did not detect any pathogens but contained a lymphocytic predominance. Chest radiograph revealed diffuse reticulonodular opacities (Fig. 1a). Computed tomography of the chest demonstrated a non-specific pattern of interstitial prominence in both lungs sparing the apices and the extreme periphery (Fig. 1b). Spirometry and lung volumes were suggestive of a restrictive defect that worsened over time (Table 1). Due to concerns about his technique, he underwent a E75
Garrod et al.
a
c
b
Fig. 1. (a) Chest radiograph demonstrating bilateral reticular nodular opacities in both lungs, predominantly the lung base. (b) Computed tomography scan of the chest with intravenous contrast (obtained two wk after the plain radiograph), demonstrating interstitial prominence mainly in the lower portions of both lungs with sparing of the apices, mild ground-glass opacity and no confluent opacities or nodules. No evidence of mosaic perfusion on expiratory imaging (not shown). (c) Chest radiograph eight months later, demonstrating near complete resolution of the reticulonodular lung pattern. Table 1. Lung function testing results Time from stopping sirolimus
3 months before
1.5 months before
3 wk before*
2 wk before
2 months after
FVC FEV1 FEF25–75 TLC SpO2
52 52 66 56 92
40 39 48 52 94
69 68 >62
32 32 41
84 84 112
94
99
*Forced deflation.
forced deflation spirometry test while under anesthesia for a bone marrow aspirate. This confirmed a restrictive defect, although less severe. He also performed a six-minute walk test with distance of 52% predicted and lowest saturation during testing of 86%. Open lung biopsy was considered but deferred based on anticipated risk-benefit ratio. The patient’s extensive medication list was reviewed for possible agents associated with ILD. The list included oral budesonide, megestrol acetate, potassium chloride, ranitidine, acyclovir, amlodipine, cholecalciferol, fluconazole, penicillin, prednisone, sirolimus, calcium, multivitamins, omega fatty acids, and isradipine, and intravenous immunoglobulin, infliximab, and pentamidine. Based on reports of sirolimus-induced ILD in SOT recipients, a working diagnosis of druginduced ILD was made and the medication was discontinued. The patient had been on this medication for over 1.5 yr, with sirolimus levels ranging from
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12438
Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation Garrod AS, Goyal RK, Weiner DJ. (2015) Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation. Pediatr Transplant, 19: E75–E77. DOI: 10.1111/petr.12438. Abstract: Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported.
Andrea S. Garrod1, Rakesh K. Goyal2 and Daniel J. Weiner3 1
Division of Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA, 2Blood and Marrow Transplantation and Cellular Therapies, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA, 3Divisions of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics,Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Key words: pediatrics – hematopoietic stem cell transplantation – sirolimus – interstitial lung disease – lung function tests Daniel J. Weiner, MD, Division of Pulmonary Medicine, Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Tel.: +1 412 692 5630 Fax: +1 412 692 6645 E-mail: [email protected] Accepted for publication 9 January 2015
Sirolimus is an immunosuppressive medication used commonly for prophylaxis and treatment of graft-versus-host disease in SOT and allogeneic HCT patients (1). Side effects include thrombocytopenia, hyperlipidemia, and rarely pulmonary toxicity (2). The vast majority of the respiratory complications have been reported in adult SOT patients (3) and have never been reported in a pediatric HCT patient. When interstitial pneumonitis develops, patients present with symptoms including dyspnea, fatigue, fever, and rarely hemoptysis (3). Chest radiography and computed tomography scans are characterized by bilateral interstitial infiltrates. Bronchoalveolar lavage fluid typically indicates a lymphocytic alveolitis and rarely shows evidence of hemorrhage. Pulmonary function testing demonstrates a restrictive defect reflecting the interstitial findings (2).
Abbreviations: HCT, hematopoietic stem cell transplantation; ILD, interstitial lung disease; SOT, solid organ transplant.
Case history
An eight-yr-old boy with a history of acute lymphoblastic leukemia and subsequent myelodysplastic syndrome underwent allogeneic matched HCT. His post-transplantation course was complicated by severe acute and chronic graft-versushost disease of the skin and gut which was treated with sirolimus. Two yr after transplant, he was noted to have nocturnal hypoxemia and polycythemia while hospitalized for Clostridium difficile colitis. He reported dyspnea and dry cough with exercise, and examination was notable for digital clubbing. A bronchoalveolar lavage was performed which did not detect any pathogens but contained a lymphocytic predominance. Chest radiograph revealed diffuse reticulonodular opacities (Fig. 1a). Computed tomography of the chest demonstrated a non-specific pattern of interstitial prominence in both lungs sparing the apices and the extreme periphery (Fig. 1b). Spirometry and lung volumes were suggestive of a restrictive defect that worsened over time (Table 1). Due to concerns about his technique, he underwent a E75
Garrod et al.
a
c
b
Fig. 1. (a) Chest radiograph demonstrating bilateral reticular nodular opacities in both lungs, predominantly the lung base. (b) Computed tomography scan of the chest with intravenous contrast (obtained two wk after the plain radiograph), demonstrating interstitial prominence mainly in the lower portions of both lungs with sparing of the apices, mild ground-glass opacity and no confluent opacities or nodules. No evidence of mosaic perfusion on expiratory imaging (not shown). (c) Chest radiograph eight months later, demonstrating near complete resolution of the reticulonodular lung pattern. Table 1. Lung function testing results Time from stopping sirolimus
3 months before
1.5 months before
3 wk before*
2 wk before
2 months after
FVC FEV1 FEF25–75 TLC SpO2
52 52 66 56 92
40 39 48 52 94
69 68 >62
32 32 41
84 84 112
94
99
*Forced deflation.
forced deflation spirometry test while under anesthesia for a bone marrow aspirate. This confirmed a restrictive defect, although less severe. He also performed a six-minute walk test with distance of 52% predicted and lowest saturation during testing of 86%. Open lung biopsy was considered but deferred based on anticipated risk-benefit ratio. The patient’s extensive medication list was reviewed for possible agents associated with ILD. The list included oral budesonide, megestrol acetate, potassium chloride, ranitidine, acyclovir, amlodipine, cholecalciferol, fluconazole, penicillin, prednisone, sirolimus, calcium, multivitamins, omega fatty acids, and isradipine, and intravenous immunoglobulin, infliximab, and pentamidine. Based on reports of sirolimus-induced ILD in SOT recipients, a working diagnosis of druginduced ILD was made and the medication was discontinued. The patient had been on this medication for over 1.5 yr, with sirolimus levels ranging from
