American Journal of Therapeutics 0, 1–4 (2016)
Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report Baran Balcan, MD,1* Ergun Simsek, MD,2 Aylin O. Ugurlu, MD,1 Ebru Demiralay, MD,3 and Sevgi Sahin, MD2
Sirolimus is a mammalian target of the rapamycin, a protein kinase, which is responsible for inhibition of T cell and B cell proliferation. Sirolimus has side effects on lugs, and may cause cryptogenic organizing pneumonia, diffuse alveolar hemorrhage, lymphocytic pneumonitis, hypersensitivity pneumonitis, desquamative interstitial pneumonia, and pulmonary alveolar proteinosis. Diagnosis is based on the combination of clinical, radiological, histological, and pathological investigation. We report a case of diffuse alveolar hemorrhage in a 33-year-old, female renal transplant recipient. After discontinuation of sirolimus, radiological images and clinical condition of the patient got better. We also planned steroid therapy for 6 months by tapering the dosage slowly. After steroid therapy, full recovery of pulmonary functions achieved, and the patient is observed in our outpatient clinic with lack of any pulmonary symptoms. Keywords: sirolimus, lung, hemorrhage, steroid
INTRODUCTION Kidney transplantation is the definite treatment of end-stage renal disease. Immunosuppressive treatment is necessary for the transplanted organ not to be rejected by the recipient. An important point in immunosuppressive treatment is the side effects on other organs. Sirolimus and everolimus are the mammalian targets of the rapamycin, a protein kinase, which is responsible for inhibition of T and B cell proliferation.1–3 Recently we treated a 33-year-old female patient with sirolimus-induced diffuse alveolar hemorrhage (DAH). She was first diagnosed with pneumonia and underwent antibiotic therapy. After no improvement in her clinical condition, bronchoscopy was performed.
Departments of 1Pulmonary Medicine, 2Nephrology, and 3Pathology, Faculty of Medicine, Baskent University, Istanbul, Turkey. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Pulmonary Medicine, Faculty of Medicine, Baskent University, Istanbul 34100, Turkey. E-mail: [email protected]
Pathology result of bronchoalveolar lavage (BAL) material was hemosiderin-loaded macrophages. The aim of this report was performing bronchoscopy immediately for definite diagnosis to immunsupressed patients due to solid organ transplantation and not loosing time with antibiotic treatment for pneumonia.
CASE We discussed a 33-year-old, female renal transplant recipient. She provided consent for this case report. She came to emergency department with fever, cough, and sputum. She was subfebrile (37.5), tachycardic (102 per minute), normotensive (110/70) tachypneic (30 per minute), and desaturated (90%). In physical examination; there was bilateral fine ralles and bilateral +1 pretibial edema; the other systemic examination was normal. In her chest x-ray and computed tomography, there was bilateral diffuse patchy infiltration (Figure 1). She was hospitalized with the diagnosis of pneumonia and parenteral antibiotic therapy was started with moxifloxacin. In the 48th hour of antibiotic treatment, her fever and inflammatory markers, such as erythrocyte sedimentation rate,
1075–2765 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Balcan et al
2
FIGURE 1. Bilateral patchy infiltration in computed tomography images.
c-reactive protein, were still high, and she was consulted to pulmonary division. We evaluated the patient and performed bronchoscopy. Increased capillarity, mucosal fragility, and disseminated hemorrhage were observed during bronchoscopy. Transbronchial biopsy was avoided, because of serious desaturation during the procedure, only BAL was performed. Bacterial, mycobacterium tuberculosis, fungal cultures, influenza, and galactomannan antigen tests were studied. After bronchoscopy, antibiotic treatment upgraded to carbapenem + fluoroquinolone (ciprofloxacin) + antifungal
(amphotericin B). All culture results were negative. Although we started new antibiotics, there was no improvement in her clinical condition. At the same time, the level of serum sirolimus was higher than the normal range. Pathology result of the patient was reported as hemosiderin-loaded macrophages, eosinophil predominancy, and few lymphocytes, consistent with DAH due to sirolimus (Figure 2). We discontinued sirolimus and started pulse steroid (1 g/d methylprednisolone) for 3 days. In the following period, her oxygen supply declined immediately and clinical condition of the patient got better. After 2 weeks, we discharged the patient and continued methylprednisolone treatment in 1 mg$kg21$d21 dosage. During her follow-up, pulmonary symptoms and radiological images got better (Figure 3). We are planning to continue steroid treatment for 6 months by tapering the dosage slowly.
DISCUSSION
FIGURE 2. Hemosiderin loaded macrophages pointed in bronchio-alveolar lavage specimen. American Journal of Therapeutics (2016) 0(0)
are
mTOR receptor analogs inhibit T cell and B cell proliferation, so patients using sirolimus and everolimus become vulnerable to opportunistic infections.1,2 These drugs may cause direct organ toxicity,4 and by destroying the antineoplastic functions in vivo they can be the reason of newly diagnosed malignancies.5,6 Pulmonary toxicity can be seen up to 11% using mTOR receptor analogs.7 Most seen complications in the lung secondary to these immunosuppressive drugs are bronchiolitis obliterans organizing pneumonia, DAH, and lymphocytic www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Diffuse Alveolar Hemorrhage
3
FIGURE 3. Computed tomography images after therapy.
pneumonitis.4,7,8 In addition, hypersensitivity pneumonitis, desquamative interstitial pneumonia, and pulmonary alveolar proteinosis can also be seen.8–10 Cytologic evaluation of BAL may be helpful in alveolar hemorrhage, but there is not a specific sign for sirolimus toxicity. It can occur as primary alveolar hemorrhage or secondary to infections, toxic gas inhalation, volume overload, and venous congestion due to renal or cardiac failure. It is important to eliminate infection from noninfectious causes.11 In hypersensitivity pneumonitis; eosinophilic predominancy, in bronchiolitis obliterans organizing pneumonia; lymphocytic predominancy, in massive alveolar edema and bleeding; hemosiderinloaded macrophages can be seen.12,13 Chest x-ray or computed tomography images can look such as pneumonitic infiltration or acute alveolar edema in these patients, therefore, first attempt of clinicians is starting antibiotics and diuretic therapy.12 Usually broad-spectrum antibiotics are started, and with diuresis or dialysis, negative fluid balance is maintained. In our case, although we started broad-spectrum antibiotics and had negative fluid balance with diuresis, there was no satisfactory improvement in pulmonary symptoms. We performed bronchoscopy to eliminate infections as recommended in the literature. Microbiological evaluation of BAL fluid analysis was performed. Hemosiderin-loaded macrophages was observed consistent with DAH. Biopsy was avoided because of disseminated hemorrhage. Sirolimus should be stopped immediately after diagnosing pulmonary toxicity.14,15 We already stopped www.americantherapeutics.com
sirolimus in our case because its serum level was over the normal range. In addition to discontinuation of drug, clinicians should consider starting steroids. In our case, we started with pulse steroid, then continued methylprednisolone in 1 mg$kg21$d21 by tapering the dosage slowly. Although we observed hemosiderinloaded macrophages in pathology, we could not eliminate cryptogenic organizing pneumonia (COP). Besides DAH, patchy infiltrations in radiological images and eosinophilic predominancy can also be seen in COP. Most valuable diagnostic method in differentiation of COP from DAH is biopsy, but we could not perform transbronchial biopsy due to serious bleeding and desaturation during bronchoscopy procedure. Because distinction of DAH from COP, impossible by radiological imaging without performing biopsy and although it is not evidence based, when steroid is started, faster healing and better prognosis can be achieved, we preferred steroid therapy for a longer period.16,17 In conclusion, in the presence of respiratory symptoms in renal transplant recipients pulmonary toxicity should be considered if they are using mTOR receptor analogs. Signs and symptoms of a patient who has sirolimus-induced DAH cannot be differentiated radiologically from acute alveolar edema or pneumonia at first. Bronchoscopic biopsy and BAL analysis are helpful for the diagnosis. Discontinuation of the drug is the key point in treatment of pulmonary toxicity. Steroids should be started in the necessary doses American Journal of Therapeutics (2016) 0(0)
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
4
according to the type of toxicity. Sirolimus-induced DAH can be diagnosed definitely by stopping the drug, and with or without steroid waiting for the improvement in the clinical condition.
REFERENCES 1. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The rapamune us study group. Lancet. 2000;356:194–202. 2. Chapman JR, Valantine H, Albanell J, et al. Proliferation signal inhibitors in transplantation: questions at the cutting edge of everolimus therapy. Transplant Proc. 2007;39: 2937–2950. 3. Campistol JM, Albanell J, Arns W, et al. Use of proliferation signal inhibitors in the management of posttransplant malignancies–clinical guidance. Nephrol Dial Transplant. 2007;22(Suppl 1):i36–41. 4. Champion L, Stern M, Israel-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med. 2006;144:505–509. 5. Boratynska M, Zmonarski SC, Klinger M. Reccurence of kaposi’s sarcoma after increased exposure to sirolimus. Int Immunopharmacol. 2006;6:2018–2022. 6. Cullis B, D’Souza R, McCullagh P, et al. Sirolimusinduced remission of posttransplantation lymphoproliferative disorder. Am J Kidney Dis. 2006;47:e67–72. 7. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant. 2007;22:3631–3637.
American Journal of Therapeutics (2016) 0(0)
Balcan et al 8. Pham PT, Pham PC, Danovitch GM, et al. Sirolimusassociated pulmonary toxicity. Transplantation. 2004;77: 1215–1220. 9. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med. 2000;343:225–226. 10. Flores-Franco RA, Luevano-Flores E, Gaston-Ramirez C. Sirolimus-associated desquamative interstitial pneumonia. Respiration. 2007;74:237–238. 11. Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant. 2007;26: 652–657. 12. Kirby S, Satoskar A, Brodsky S, et al. Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens. Diagn Pathol. 2012;7:25. 13. Hashemi-Sadraei N, Sadrpour S, Baram D, et al. Sirolimus-associated diffuse alveolar hemorrhage in a renal transplant recipient on long-term anticoagulation. Clin Nephrol. 2007;68:238–244. 14. Pham PT, Pham PC, Danovitch GM, et al. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. Am J Transplant. 2005;5:2565–2569. 15. Damas C, Oliveira A, Morais A. Lung toxicity induced by rapamycin [In Portuguese]. Rev Port Pneumol. 2006;12: 715–724. 16. Junpaparp P, Sharma B, Samiappan A, et al. Everolimus-induced severe pulmonary toxicity with diffuse alveolar hemorrhage. Ann Am Thorac Soc. 2013;10: 727–729. 17. Vandewiele B, Vandecasteele SJ, Vanwalleghem L, et al. Diffuse alveolar hemorrhage induced by everolimus. Chest. 2010;137:456–459.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report Baran Balcan, MD,1* Ergun Simsek, MD,2 Aylin O. Ugurlu, MD,1 Ebru Demiralay, MD,3 and Sevgi Sahin, MD2
Sirolimus is a mammalian target of the rapamycin, a protein kinase, which is responsible for inhibition of T cell and B cell proliferation. Sirolimus has side effects on lugs, and may cause cryptogenic organizing pneumonia, diffuse alveolar hemorrhage, lymphocytic pneumonitis, hypersensitivity pneumonitis, desquamative interstitial pneumonia, and pulmonary alveolar proteinosis. Diagnosis is based on the combination of clinical, radiological, histological, and pathological investigation. We report a case of diffuse alveolar hemorrhage in a 33-year-old, female renal transplant recipient. After discontinuation of sirolimus, radiological images and clinical condition of the patient got better. We also planned steroid therapy for 6 months by tapering the dosage slowly. After steroid therapy, full recovery of pulmonary functions achieved, and the patient is observed in our outpatient clinic with lack of any pulmonary symptoms. Keywords: sirolimus, lung, hemorrhage, steroid
INTRODUCTION Kidney transplantation is the definite treatment of end-stage renal disease. Immunosuppressive treatment is necessary for the transplanted organ not to be rejected by the recipient. An important point in immunosuppressive treatment is the side effects on other organs. Sirolimus and everolimus are the mammalian targets of the rapamycin, a protein kinase, which is responsible for inhibition of T and B cell proliferation.1–3 Recently we treated a 33-year-old female patient with sirolimus-induced diffuse alveolar hemorrhage (DAH). She was first diagnosed with pneumonia and underwent antibiotic therapy. After no improvement in her clinical condition, bronchoscopy was performed.
Departments of 1Pulmonary Medicine, 2Nephrology, and 3Pathology, Faculty of Medicine, Baskent University, Istanbul, Turkey. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Pulmonary Medicine, Faculty of Medicine, Baskent University, Istanbul 34100, Turkey. E-mail: [email protected]
Pathology result of bronchoalveolar lavage (BAL) material was hemosiderin-loaded macrophages. The aim of this report was performing bronchoscopy immediately for definite diagnosis to immunsupressed patients due to solid organ transplantation and not loosing time with antibiotic treatment for pneumonia.
CASE We discussed a 33-year-old, female renal transplant recipient. She provided consent for this case report. She came to emergency department with fever, cough, and sputum. She was subfebrile (37.5), tachycardic (102 per minute), normotensive (110/70) tachypneic (30 per minute), and desaturated (90%). In physical examination; there was bilateral fine ralles and bilateral +1 pretibial edema; the other systemic examination was normal. In her chest x-ray and computed tomography, there was bilateral diffuse patchy infiltration (Figure 1). She was hospitalized with the diagnosis of pneumonia and parenteral antibiotic therapy was started with moxifloxacin. In the 48th hour of antibiotic treatment, her fever and inflammatory markers, such as erythrocyte sedimentation rate,
1075–2765 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Balcan et al
2
FIGURE 1. Bilateral patchy infiltration in computed tomography images.
c-reactive protein, were still high, and she was consulted to pulmonary division. We evaluated the patient and performed bronchoscopy. Increased capillarity, mucosal fragility, and disseminated hemorrhage were observed during bronchoscopy. Transbronchial biopsy was avoided, because of serious desaturation during the procedure, only BAL was performed. Bacterial, mycobacterium tuberculosis, fungal cultures, influenza, and galactomannan antigen tests were studied. After bronchoscopy, antibiotic treatment upgraded to carbapenem + fluoroquinolone (ciprofloxacin) + antifungal
(amphotericin B). All culture results were negative. Although we started new antibiotics, there was no improvement in her clinical condition. At the same time, the level of serum sirolimus was higher than the normal range. Pathology result of the patient was reported as hemosiderin-loaded macrophages, eosinophil predominancy, and few lymphocytes, consistent with DAH due to sirolimus (Figure 2). We discontinued sirolimus and started pulse steroid (1 g/d methylprednisolone) for 3 days. In the following period, her oxygen supply declined immediately and clinical condition of the patient got better. After 2 weeks, we discharged the patient and continued methylprednisolone treatment in 1 mg$kg21$d21 dosage. During her follow-up, pulmonary symptoms and radiological images got better (Figure 3). We are planning to continue steroid treatment for 6 months by tapering the dosage slowly.
DISCUSSION
FIGURE 2. Hemosiderin loaded macrophages pointed in bronchio-alveolar lavage specimen. American Journal of Therapeutics (2016) 0(0)
are
mTOR receptor analogs inhibit T cell and B cell proliferation, so patients using sirolimus and everolimus become vulnerable to opportunistic infections.1,2 These drugs may cause direct organ toxicity,4 and by destroying the antineoplastic functions in vivo they can be the reason of newly diagnosed malignancies.5,6 Pulmonary toxicity can be seen up to 11% using mTOR receptor analogs.7 Most seen complications in the lung secondary to these immunosuppressive drugs are bronchiolitis obliterans organizing pneumonia, DAH, and lymphocytic www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Diffuse Alveolar Hemorrhage
3
FIGURE 3. Computed tomography images after therapy.
pneumonitis.4,7,8 In addition, hypersensitivity pneumonitis, desquamative interstitial pneumonia, and pulmonary alveolar proteinosis can also be seen.8–10 Cytologic evaluation of BAL may be helpful in alveolar hemorrhage, but there is not a specific sign for sirolimus toxicity. It can occur as primary alveolar hemorrhage or secondary to infections, toxic gas inhalation, volume overload, and venous congestion due to renal or cardiac failure. It is important to eliminate infection from noninfectious causes.11 In hypersensitivity pneumonitis; eosinophilic predominancy, in bronchiolitis obliterans organizing pneumonia; lymphocytic predominancy, in massive alveolar edema and bleeding; hemosiderinloaded macrophages can be seen.12,13 Chest x-ray or computed tomography images can look such as pneumonitic infiltration or acute alveolar edema in these patients, therefore, first attempt of clinicians is starting antibiotics and diuretic therapy.12 Usually broad-spectrum antibiotics are started, and with diuresis or dialysis, negative fluid balance is maintained. In our case, although we started broad-spectrum antibiotics and had negative fluid balance with diuresis, there was no satisfactory improvement in pulmonary symptoms. We performed bronchoscopy to eliminate infections as recommended in the literature. Microbiological evaluation of BAL fluid analysis was performed. Hemosiderin-loaded macrophages was observed consistent with DAH. Biopsy was avoided because of disseminated hemorrhage. Sirolimus should be stopped immediately after diagnosing pulmonary toxicity.14,15 We already stopped www.americantherapeutics.com
sirolimus in our case because its serum level was over the normal range. In addition to discontinuation of drug, clinicians should consider starting steroids. In our case, we started with pulse steroid, then continued methylprednisolone in 1 mg$kg21$d21 by tapering the dosage slowly. Although we observed hemosiderinloaded macrophages in pathology, we could not eliminate cryptogenic organizing pneumonia (COP). Besides DAH, patchy infiltrations in radiological images and eosinophilic predominancy can also be seen in COP. Most valuable diagnostic method in differentiation of COP from DAH is biopsy, but we could not perform transbronchial biopsy due to serious bleeding and desaturation during bronchoscopy procedure. Because distinction of DAH from COP, impossible by radiological imaging without performing biopsy and although it is not evidence based, when steroid is started, faster healing and better prognosis can be achieved, we preferred steroid therapy for a longer period.16,17 In conclusion, in the presence of respiratory symptoms in renal transplant recipients pulmonary toxicity should be considered if they are using mTOR receptor analogs. Signs and symptoms of a patient who has sirolimus-induced DAH cannot be differentiated radiologically from acute alveolar edema or pneumonia at first. Bronchoscopic biopsy and BAL analysis are helpful for the diagnosis. Discontinuation of the drug is the key point in treatment of pulmonary toxicity. Steroids should be started in the necessary doses American Journal of Therapeutics (2016) 0(0)
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
4
according to the type of toxicity. Sirolimus-induced DAH can be diagnosed definitely by stopping the drug, and with or without steroid waiting for the improvement in the clinical condition.
REFERENCES 1. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The rapamune us study group. Lancet. 2000;356:194–202. 2. Chapman JR, Valantine H, Albanell J, et al. Proliferation signal inhibitors in transplantation: questions at the cutting edge of everolimus therapy. Transplant Proc. 2007;39: 2937–2950. 3. Campistol JM, Albanell J, Arns W, et al. Use of proliferation signal inhibitors in the management of posttransplant malignancies–clinical guidance. Nephrol Dial Transplant. 2007;22(Suppl 1):i36–41. 4. Champion L, Stern M, Israel-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med. 2006;144:505–509. 5. Boratynska M, Zmonarski SC, Klinger M. Reccurence of kaposi’s sarcoma after increased exposure to sirolimus. Int Immunopharmacol. 2006;6:2018–2022. 6. Cullis B, D’Souza R, McCullagh P, et al. Sirolimusinduced remission of posttransplantation lymphoproliferative disorder. Am J Kidney Dis. 2006;47:e67–72. 7. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant. 2007;22:3631–3637.
American Journal of Therapeutics (2016) 0(0)
Balcan et al 8. Pham PT, Pham PC, Danovitch GM, et al. Sirolimusassociated pulmonary toxicity. Transplantation. 2004;77: 1215–1220. 9. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med. 2000;343:225–226. 10. Flores-Franco RA, Luevano-Flores E, Gaston-Ramirez C. Sirolimus-associated desquamative interstitial pneumonia. Respiration. 2007;74:237–238. 11. Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant. 2007;26: 652–657. 12. Kirby S, Satoskar A, Brodsky S, et al. Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens. Diagn Pathol. 2012;7:25. 13. Hashemi-Sadraei N, Sadrpour S, Baram D, et al. Sirolimus-associated diffuse alveolar hemorrhage in a renal transplant recipient on long-term anticoagulation. Clin Nephrol. 2007;68:238–244. 14. Pham PT, Pham PC, Danovitch GM, et al. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. Am J Transplant. 2005;5:2565–2569. 15. Damas C, Oliveira A, Morais A. Lung toxicity induced by rapamycin [In Portuguese]. Rev Port Pneumol. 2006;12: 715–724. 16. Junpaparp P, Sharma B, Samiappan A, et al. Everolimus-induced severe pulmonary toxicity with diffuse alveolar hemorrhage. Ann Am Thorac Soc. 2013;10: 727–729. 17. Vandewiele B, Vandecasteele SJ, Vanwalleghem L, et al. Diffuse alveolar hemorrhage induced by everolimus. Chest. 2010;137:456–459.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
