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Pulmonary, Critical Care, and Sleep Pearls
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An Unusual Cause of Respiratory Failure in a 25-Year-Old Heart and Lung Transplant Recipient Sarah Narotzky, MD; Cassie Colleen Kennedy, MD, FCCP; and Fabien Maldonado, MD, FCCP
A 25-year-old woman, a never smoker with a history of heart-lung transplantation for World Health Organization group 1 pulmonary arterial hypertension performed 20 months prior to presentation, was evaluated for shortness of breath. Following transplantation, she was initiated on standard therapy of prednisone, tacrolimus, and azathioprine, along with routine antimicrobial prophylaxis. Her posttransplant course was complicated by persistent acute cellular rejection, as determined from a transbronchial biopsy specimen, without evidence of rejection in an endomyocardial biopsy specimen. The immunosuppressive medications were supplemented with pulse-dosed steroids, and the patient was transitioned from azathioprine to mycophenolate mofetil. Sirolimus was added 9 months prior to presentation. Three months prior to presentation, she was admitted for increasing oxygen requirements, shortness of breath, and bilateral infiltrates on the CT scans of the chest.
CHEST 2015; 147(5):e185-e188
Physical Examination Findings The patient was afebrile with a heart rate of 89 beats/min, BP of 124/82 mm Hg, respiratory rate of 20 breaths/min, and an oxygen saturation of 85% on room air and 94% on 2 L of oxygen. She was alert, oriented, and in mild respiratory distress. Examination revealed a clear oropharynx with moist mucosa. The neck examination showed no jugular venous distention, and lung auscultation revealed scattered, fine inspiratory crackles over the lung fields bilaterally. The heart rate and rhythm were regular with no murmur, gallop, or rub. There was no clubbing or cyanosis, but trace peripheral edema was present. The patient was noted to have mild wasting of muscles diffusely and appeared slightly Cushingoid.
Diagnostic Studies The chest CT scan without IV contrast revealed diffuse ground-glass infiltrates with thickening of the alveolar septa in upper and mid-lung zone predominance (Fig 1). Pulmonary function testing revealed a restrictive pattern Manuscript received June 13, 2014; revision accepted September 25, 2014. AFFILIATIONS: From Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. CORRESPONDENCE TO: Fabien Maldonado, MD, FCCP, Mayo Clinic College of Medicine - Pulmonary/CCM, 200 1st St SW, Rochester, MN 55905; e-mail: [email protected]
Figure 1 – A, B, Different slices from a CT scan of the chest demonstrate diffuse ground-glass infiltrates with alveolar septal thickening.
with a total lung capacity of 2.98 L (63% predicted) and a diffusion capacity of 33% predicted. Compared with prior pulmonary function testings, there had been a significant decline in total lung capacity and diffusion capacity of the lung for carbon monoxide. Bronchoscopy was performed. Transbronchial biopsy specimens revealed scattered intraalveolar foamy histiocytes and edema fluid (Fig 2). The bronchoalveolar fluid was described as cloudy. A periodic acid-Schiff stain was positive. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1443 © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.
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Figure 2 – Hematoxylin and eosin stain showing scattered intraalveolar foamy histiocytes and edema fluid (original magnification 3 400).
What is the diagnosis?
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147#5 CHEST MAY 2015
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Diagnosis: Pulmonary alveolar proteinosis secondary to sirolimus Discussion Pulmonary alveolar proteinosis (PAP) is a disorder caused by the accumulation of lipoproteinaceous material in the alveoli and bronchioles, resulting in symptoms of dyspnea and nonproductive cough. PAP is a rare disorder, with approximately 500 cases reported in the literature since 2007. A small subset of PAP cases will resolve spontaneously, while most either remain stable or progressively worsen and require treatment. Diagnosis of PAP is generally made with bronchoscopy. BAL typically yields a milky-white fluid, and lung biopsy specimens show foamy macrophages with PAS stain. Biopsies can also demonstrate eosinophilic material with surfactant protein on immunohistochemistry. Causes for PAP are usually divided into three categories: primary, secondary, and congenital. Most cases of primary PAP are secondary to autoantibodies against granulocyte-macrophage colony stimulating factor (GM-CSF), leading to impaired alveolar macrophage function, deficient surfactant processing, and eventual alveolar accumulation. Secondary PAP has been associated with malignancies, inhaled toxins, immunodeficiency, immunosuppression, and infections. Congenital PAP generally presents during childhood and typically results from inherited defects in surfactant processing. The treatment of PAP depends on the etiology. For secondary, or acquired PAP, removal of the offending agent is mandatory in addition to whole lung lavage (WLL), which should be considered as first-line therapy in cases of respiratory failure. Therapy with GM-CSF has been proposed in patients with PAP, although typically reserved for patients with primary PAP. Sirolimus is a mammalian target of rapamycin inhibitor first introduced for use in transplantation in 1999. This agent inhibits cell-cycle progression in lymphocytes, fibroblasts, and endothelial cells by blocking transduction signals from the IL-2 receptor to the nucleus. While sirolimus is less nephrotoxic than the calcineurin inhibitors, it has been associated with multiple types of lung toxicities, including interstitial pneumonitis, organizing pneumonia, diffuse alveolar hemorrhage, and, rarely, PAP. Cases of sirolimus-related lung toxicity in solid-organ recipients have been reported, including interstitial pneumonitis, alveolar hemorrhage, and organizing pneumonia. PAP secondary to sirolimus therapy was
described in only four other lung transplant patients to date, all of whom had complete recovery after discontinuation of the inciting medication. Morelon and colleagues have proposed specific criteria for sirolimus-related lung toxicity, including exposure to sirolimus when pulmonary symptoms developed, exclusion of infection and other inciting agents and resolution after withdrawal or reduction of the drug dose. Risk factors for sirolimus-related lung toxicity have not been clearly established, though high doses of sirolimus, exposure to this agent after toxicity to other drugs, and male sex may be correlated. The typical age of presentation for sirolimus-related PAP is 30 to 50 years. The natural history of PAP is variable, though most patients with secondary PAP due to treatable disease or drug toxicity have favorable outcomes. The majority of deaths are secondary to respiratory failure and unusual infections such as those by Nocardia species, fungal infections, and Mycobacterium species. Clinical Course
The sirolimus was discontinued at the time of hospitalization, given concern for sirolimus-induced lung injury. The patient was started on GM-CSF therapy with the aim of enhancing the resolution of this disease by increasing macrophage function (250 mg by nebulizer bid). Because of significant respiratory distress, the decision was made to proceed with WLL. A total of 19 L of normal saline was instilled sequentially into both lungs using double-lumen endotracheal intubation. The lavage return was initially milky but progressively cleared. Chest radiographs revealed resolution of the infiltrates after WLL (Fig 3), though she did require two subsequent WLLs. Serum autoantibodies against GM-CSF were eventually checked and found to be absent. Because of a favorable clinical course, treatment with GM-CSF supplementation was continued, though in the absence of clear evidence for benefit in this situation. Nearly 1 year after the last WLL, she continues to have
Figure 3 – A, B, Chest radiographs before (A) and after (B) treatment, demonstrating complete resolution of the parenchymal infiltrates.
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minimal acute rejection (International Society for Heart & Lung Transplantation grade A1), but is asymptomatic from a respiratory standpoint and has had complete resolution of the bilateral infiltrates noted on previous chest imaging. Sirolimus has not been reintroduced to date.
Acknowledgments
Clinical Pearls
Suggested Readings
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
1. PAP is caused by accumulation of lipoproteinaceous material in alveoli and bronchioles, with symptoms of dyspnea and a nonproductive cough.
Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000;55(1):67-77.
2. Primary PAP is associated with autoantibodies against GM-CSF, while secondary PAP is related to immunosuppressive therapy, malignancy, and infection. The diagnosis is made with bronchoscopy, BAL, and lung biopsy specimens.
Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation. 2004;77(8):1215-1220.
3. Sirolimus has been associated with a number of pulmonary complications, including interstitial pneumonitis, alveolar hemorrhage, and organizing pneumonia. Although uncommon, secondary PAP should be added to this list as well.
Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimusassociated interstitial pneumonitis in renal transplant patients. Transplantation. 2001;72(5):787-790.
Garrean S, Massad MG, Tshibaka M, Hanhan Z, Caines AE, Benedetti E. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant. 2005;19(5):698-703. Pedroso SL, Martins LS, Sousa S, et al. Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus. Transpl Int. 2007;20(3):291-296. Kadikoy H, Paolini M, Achkar K, et al. Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus. Nephrol Dial Transplant. 2010;25(8):2795-2798.
e188 Pulmonary, Critical Care, and Sleep Pearls Downloaded From: http://journal.publications.chestnet.org/ by a University of Iowa User on 05/24/2015
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147#5 CHEST MAY 2015
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Pulmonary, Critical Care, and Sleep Pearls
]
An Unusual Cause of Respiratory Failure in a 25-Year-Old Heart and Lung Transplant Recipient Sarah Narotzky, MD; Cassie Colleen Kennedy, MD, FCCP; and Fabien Maldonado, MD, FCCP
A 25-year-old woman, a never smoker with a history of heart-lung transplantation for World Health Organization group 1 pulmonary arterial hypertension performed 20 months prior to presentation, was evaluated for shortness of breath. Following transplantation, she was initiated on standard therapy of prednisone, tacrolimus, and azathioprine, along with routine antimicrobial prophylaxis. Her posttransplant course was complicated by persistent acute cellular rejection, as determined from a transbronchial biopsy specimen, without evidence of rejection in an endomyocardial biopsy specimen. The immunosuppressive medications were supplemented with pulse-dosed steroids, and the patient was transitioned from azathioprine to mycophenolate mofetil. Sirolimus was added 9 months prior to presentation. Three months prior to presentation, she was admitted for increasing oxygen requirements, shortness of breath, and bilateral infiltrates on the CT scans of the chest.
CHEST 2015; 147(5):e185-e188
Physical Examination Findings The patient was afebrile with a heart rate of 89 beats/min, BP of 124/82 mm Hg, respiratory rate of 20 breaths/min, and an oxygen saturation of 85% on room air and 94% on 2 L of oxygen. She was alert, oriented, and in mild respiratory distress. Examination revealed a clear oropharynx with moist mucosa. The neck examination showed no jugular venous distention, and lung auscultation revealed scattered, fine inspiratory crackles over the lung fields bilaterally. The heart rate and rhythm were regular with no murmur, gallop, or rub. There was no clubbing or cyanosis, but trace peripheral edema was present. The patient was noted to have mild wasting of muscles diffusely and appeared slightly Cushingoid.
Diagnostic Studies The chest CT scan without IV contrast revealed diffuse ground-glass infiltrates with thickening of the alveolar septa in upper and mid-lung zone predominance (Fig 1). Pulmonary function testing revealed a restrictive pattern Manuscript received June 13, 2014; revision accepted September 25, 2014. AFFILIATIONS: From Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. CORRESPONDENCE TO: Fabien Maldonado, MD, FCCP, Mayo Clinic College of Medicine - Pulmonary/CCM, 200 1st St SW, Rochester, MN 55905; e-mail: [email protected]
Figure 1 – A, B, Different slices from a CT scan of the chest demonstrate diffuse ground-glass infiltrates with alveolar septal thickening.
with a total lung capacity of 2.98 L (63% predicted) and a diffusion capacity of 33% predicted. Compared with prior pulmonary function testings, there had been a significant decline in total lung capacity and diffusion capacity of the lung for carbon monoxide. Bronchoscopy was performed. Transbronchial biopsy specimens revealed scattered intraalveolar foamy histiocytes and edema fluid (Fig 2). The bronchoalveolar fluid was described as cloudy. A periodic acid-Schiff stain was positive. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1443 © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by a University of Iowa User on 05/24/2015
e185
Figure 2 – Hematoxylin and eosin stain showing scattered intraalveolar foamy histiocytes and edema fluid (original magnification 3 400).
What is the diagnosis?
e186 Pulmonary, Critical Care, and Sleep Pearls Downloaded From: http://journal.publications.chestnet.org/ by a University of Iowa User on 05/24/2015
[
147#5 CHEST MAY 2015
]
Diagnosis: Pulmonary alveolar proteinosis secondary to sirolimus Discussion Pulmonary alveolar proteinosis (PAP) is a disorder caused by the accumulation of lipoproteinaceous material in the alveoli and bronchioles, resulting in symptoms of dyspnea and nonproductive cough. PAP is a rare disorder, with approximately 500 cases reported in the literature since 2007. A small subset of PAP cases will resolve spontaneously, while most either remain stable or progressively worsen and require treatment. Diagnosis of PAP is generally made with bronchoscopy. BAL typically yields a milky-white fluid, and lung biopsy specimens show foamy macrophages with PAS stain. Biopsies can also demonstrate eosinophilic material with surfactant protein on immunohistochemistry. Causes for PAP are usually divided into three categories: primary, secondary, and congenital. Most cases of primary PAP are secondary to autoantibodies against granulocyte-macrophage colony stimulating factor (GM-CSF), leading to impaired alveolar macrophage function, deficient surfactant processing, and eventual alveolar accumulation. Secondary PAP has been associated with malignancies, inhaled toxins, immunodeficiency, immunosuppression, and infections. Congenital PAP generally presents during childhood and typically results from inherited defects in surfactant processing. The treatment of PAP depends on the etiology. For secondary, or acquired PAP, removal of the offending agent is mandatory in addition to whole lung lavage (WLL), which should be considered as first-line therapy in cases of respiratory failure. Therapy with GM-CSF has been proposed in patients with PAP, although typically reserved for patients with primary PAP. Sirolimus is a mammalian target of rapamycin inhibitor first introduced for use in transplantation in 1999. This agent inhibits cell-cycle progression in lymphocytes, fibroblasts, and endothelial cells by blocking transduction signals from the IL-2 receptor to the nucleus. While sirolimus is less nephrotoxic than the calcineurin inhibitors, it has been associated with multiple types of lung toxicities, including interstitial pneumonitis, organizing pneumonia, diffuse alveolar hemorrhage, and, rarely, PAP. Cases of sirolimus-related lung toxicity in solid-organ recipients have been reported, including interstitial pneumonitis, alveolar hemorrhage, and organizing pneumonia. PAP secondary to sirolimus therapy was
described in only four other lung transplant patients to date, all of whom had complete recovery after discontinuation of the inciting medication. Morelon and colleagues have proposed specific criteria for sirolimus-related lung toxicity, including exposure to sirolimus when pulmonary symptoms developed, exclusion of infection and other inciting agents and resolution after withdrawal or reduction of the drug dose. Risk factors for sirolimus-related lung toxicity have not been clearly established, though high doses of sirolimus, exposure to this agent after toxicity to other drugs, and male sex may be correlated. The typical age of presentation for sirolimus-related PAP is 30 to 50 years. The natural history of PAP is variable, though most patients with secondary PAP due to treatable disease or drug toxicity have favorable outcomes. The majority of deaths are secondary to respiratory failure and unusual infections such as those by Nocardia species, fungal infections, and Mycobacterium species. Clinical Course
The sirolimus was discontinued at the time of hospitalization, given concern for sirolimus-induced lung injury. The patient was started on GM-CSF therapy with the aim of enhancing the resolution of this disease by increasing macrophage function (250 mg by nebulizer bid). Because of significant respiratory distress, the decision was made to proceed with WLL. A total of 19 L of normal saline was instilled sequentially into both lungs using double-lumen endotracheal intubation. The lavage return was initially milky but progressively cleared. Chest radiographs revealed resolution of the infiltrates after WLL (Fig 3), though she did require two subsequent WLLs. Serum autoantibodies against GM-CSF were eventually checked and found to be absent. Because of a favorable clinical course, treatment with GM-CSF supplementation was continued, though in the absence of clear evidence for benefit in this situation. Nearly 1 year after the last WLL, she continues to have
Figure 3 – A, B, Chest radiographs before (A) and after (B) treatment, demonstrating complete resolution of the parenchymal infiltrates.
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by a University of Iowa User on 05/24/2015
e187
minimal acute rejection (International Society for Heart & Lung Transplantation grade A1), but is asymptomatic from a respiratory standpoint and has had complete resolution of the bilateral infiltrates noted on previous chest imaging. Sirolimus has not been reintroduced to date.
Acknowledgments
Clinical Pearls
Suggested Readings
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
1. PAP is caused by accumulation of lipoproteinaceous material in alveoli and bronchioles, with symptoms of dyspnea and a nonproductive cough.
Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000;55(1):67-77.
2. Primary PAP is associated with autoantibodies against GM-CSF, while secondary PAP is related to immunosuppressive therapy, malignancy, and infection. The diagnosis is made with bronchoscopy, BAL, and lung biopsy specimens.
Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation. 2004;77(8):1215-1220.
3. Sirolimus has been associated with a number of pulmonary complications, including interstitial pneumonitis, alveolar hemorrhage, and organizing pneumonia. Although uncommon, secondary PAP should be added to this list as well.
Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimusassociated interstitial pneumonitis in renal transplant patients. Transplantation. 2001;72(5):787-790.
Garrean S, Massad MG, Tshibaka M, Hanhan Z, Caines AE, Benedetti E. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant. 2005;19(5):698-703. Pedroso SL, Martins LS, Sousa S, et al. Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus. Transpl Int. 2007;20(3):291-296. Kadikoy H, Paolini M, Achkar K, et al. Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus. Nephrol Dial Transplant. 2010;25(8):2795-2798.
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147#5 CHEST MAY 2015
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