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Case 4: bronchiolitis obliterans in a lung transplant recipient1
I NTERACTIVE G RAND R OUNDS Case 4: Bronchiolitis Obliterans in a Lung Transplant Recipient Jaime Villanueva, MD and Edward R. Garrity, MD Interactive Grand Rounds is designed to provide health care providers with the opportunity to earn CME credit by accessing the Internet at www.immunologyed.com. The program features a clinical case accompanied by a discussion of the case. CLINICAL CASE The patient is a 28-year-old woman who underwent bilateral lung transplantation on March 7, 1993, for treatment of cystic fibrosis. The patient was cytomegalovirus (CMV) negative, and her donor was CMV positive. Initial immunosuppressive therapy included intravenous cyclosporine, azathioprine, and prednisone. Complications during the early post-operative period included development of diabetes mellitus. At 2 weeks post-transplantation, routine surveillance biopsy showed mild Grade A2 cellular rejection, which resolved after a methylprednisolone pulse. Six months after transplantation, the patient developed CMV pneumonia, which responded to ganciclovir. Cytomegalovirus pneumonia recurred 9 months after transplantation, and transbronchial biopsy showed severe Grade A3/4 rejection. Bronchiolitis obliterans was diagnosed histologically. Numerous subsequent episodes of infection and rejection have since occurred. Despite changes in the patient’s From the Department of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois. Reprint requests: Edward R. Garrity, MD, Pulmonary/Critical Care Division, Department of Medicine, Loyola University Medical Center, 2160 S. First Avenue, EMS Bldg. 10/Rm 6271, Maywood, IL 60153. Telephone: 708-327-5864. Fax: 708-327-2424. E-mail: [email protected]. Manuscript received and accepted September 6, 2000. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the A. Webb Roberts Center for Continuing Education of Baylor Health Care System, Dallas, and Medsite, Inc. The A. Webb Roberts Center for Continuing Education of Baylor Health Care System, Dallas, is accredited by the ACCME to provide continuing medical education for physicians. This section is supported by an unrestricted educational grant from Fujisawa Healthcare, Inc.
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immunosuppressive regimen, she continued to manifest decreasing forced expiratory volume in 1 second (FEV1). COMMENTARY With improvements in surgical technique and immunosuppression, current 1-year survival rates following lung transplantation approach 75%.1,2 Despite improvements in early survival, development of bronchiolitis obliterans continues to limit long-term outcome in the majority of patients. At least 50% of lung transplant recipients who survive 3 months develop bronchiolitis obliterans,3 and approximately 50% of these will die of progressive respiratory failure.4 Whereas infection and graft failure are the main causes of early death, 3 bronchiolitis obliterans is the primary cause of late death after lung transplantation.2 Bronchiolitis obliterans is thought to be a form of chronic allograft rejection.2 Histologically, it is characterized by scar formation and fibrosis in the small airways, often accompanied by intimal thickening and sclerosis of vessels.3 Clinically, the disorder is defined as progressive deterioration in graft function in the absence of acute rejection, infection, or problems involving the bronchial anastomosis that could impair pulmonary function.3,5 A drop in the FEV1 of ⬎ 20% from a baseline value is considered diagnostic of the syndrome. 5,6 Epidemiologic studies have identified risk factors for bronchiolitis obliterans syndrome. A prior episode of acute cellular rejection is the single most significant risk factor.2 More frequent, severe, or longer rejection episodes also confer increased risk.2,7,8 Other potential risk factors include CMV and other viral infections, infection with atypical respiratory pathogens, younger recipient age, airway ischemia, and donor–recipient HLA mismatching, although researchers debate the importance of these factors.4 Because investigators presume that bronchiolitis obliterans is an alloimmune response, treatment strategies have focused on increasing the level of immunosuppression.5,9 Results, how-
The Journal of Heart and Lung Transplantation Volume 19, Number 10
ever, have been disappointing.2,3 Initially, patients commonly receive a methylprednisolone pulse or cytolytic therapy to alleviate bronchiolar inflammation.2 Subsequently, the maintenance immunosuppressive regimen may be modified by increasing the corticosteroid dose, substituting tacrolimus for cyclosporine, or substituting mycophenolate mofetil for azathioprine.2 Some centers have reported that converting to tacrolimus from cyclosporine has slowed or stabilized the decline in pulmonary function in up to 50% of their patients. 4 Other treatment strategies for bronchiolitis obliterans include adding methotrexate, plasmapheresis or photopheresis, total lymphoid irradiation, and inhaled cyclosporine. As with other treatments, these methods have stabilized lung function or decreased the rate of decline for short periods in some patients, but they rarely arrest the progression of the disease.2 Because episodes of acute cellular rejection may lead to the later development of bronchiolitis obliterans, some strategies have focused on aggressively preventing or limiting the occurrence of these episodes. Some success has been reported with the use of anti-lymphocyte globulin or mycophenolate mofetil in this approach.4 These agents plus tacrolimus also have shown some effectiveness in treating acute refractory rejection in several small series.4 A more recent approach involves the use of daclizumab, a monoclonal antibody directed against the interleukin-2 receptor, in the immediate post-trans-
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plantation period to prevent acute rejection without the use of anti-lymphocyte globulin.10 REFERENCES 1. Peters SG, McDougall JC, Scott JP, et al. Lung transplantation: selection of patients and analysis of outcome. Mayo Clin Proc 1997;72:85– 8. 2. Boehler A, Estenne M. Obliterative bronchiolitis after lung transplantation. Curr Opin Pulm Med 2000;6:133–9. 3. Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest 1998; 114:1411–26. 4. Garone S, Ross DJ. Bronchiolitis obliterans syndrome. Curr Opin Organ Transplant 1999;4:254 – 63. 5. Paradis I. Bronchiolitis obliterans: pathogenesis, prevention, and management. Am J Med Sci 1998;315:161–78. 6. Cooper J, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts: International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713– 6. 7. Heng D, Phil M, Sharples LD, et al. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant 1998;17:1255– 63. 8. Husain AN, Siddiqui MT, Holmes EW, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Crit Care Med 1999;159:829 –33. 9. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997;155:789 – 818. 10. Garrity ER, Villanueva J, Bhorade S. Low rate of acute lung allograft rejection after the use of Daclizumab, an Interleukin 2 receptor antibody. Transplantation 2000 (In press).
To participate in the management of this case, go to: www.ImmunologyEd.com
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immunosuppressive regimen, she continued to manifest decreasing forced expiratory volume in 1 second (FEV1). COMMENTARY With improvements in surgical technique and immunosuppression, current 1-year survival rates following lung transplantation approach 75%.1,2 Despite improvements in early survival, development of bronchiolitis obliterans continues to limit long-term outcome in the majority of patients. At least 50% of lung transplant recipients who survive 3 months develop bronchiolitis obliterans,3 and approximately 50% of these will die of progressive respiratory failure.4 Whereas infection and graft failure are the main causes of early death, 3 bronchiolitis obliterans is the primary cause of late death after lung transplantation.2 Bronchiolitis obliterans is thought to be a form of chronic allograft rejection.2 Histologically, it is characterized by scar formation and fibrosis in the small airways, often accompanied by intimal thickening and sclerosis of vessels.3 Clinically, the disorder is defined as progressive deterioration in graft function in the absence of acute rejection, infection, or problems involving the bronchial anastomosis that could impair pulmonary function.3,5 A drop in the FEV1 of ⬎ 20% from a baseline value is considered diagnostic of the syndrome. 5,6 Epidemiologic studies have identified risk factors for bronchiolitis obliterans syndrome. A prior episode of acute cellular rejection is the single most significant risk factor.2 More frequent, severe, or longer rejection episodes also confer increased risk.2,7,8 Other potential risk factors include CMV and other viral infections, infection with atypical respiratory pathogens, younger recipient age, airway ischemia, and donor–recipient HLA mismatching, although researchers debate the importance of these factors.4 Because investigators presume that bronchiolitis obliterans is an alloimmune response, treatment strategies have focused on increasing the level of immunosuppression.5,9 Results, how-
The Journal of Heart and Lung Transplantation Volume 19, Number 10
ever, have been disappointing.2,3 Initially, patients commonly receive a methylprednisolone pulse or cytolytic therapy to alleviate bronchiolar inflammation.2 Subsequently, the maintenance immunosuppressive regimen may be modified by increasing the corticosteroid dose, substituting tacrolimus for cyclosporine, or substituting mycophenolate mofetil for azathioprine.2 Some centers have reported that converting to tacrolimus from cyclosporine has slowed or stabilized the decline in pulmonary function in up to 50% of their patients. 4 Other treatment strategies for bronchiolitis obliterans include adding methotrexate, plasmapheresis or photopheresis, total lymphoid irradiation, and inhaled cyclosporine. As with other treatments, these methods have stabilized lung function or decreased the rate of decline for short periods in some patients, but they rarely arrest the progression of the disease.2 Because episodes of acute cellular rejection may lead to the later development of bronchiolitis obliterans, some strategies have focused on aggressively preventing or limiting the occurrence of these episodes. Some success has been reported with the use of anti-lymphocyte globulin or mycophenolate mofetil in this approach.4 These agents plus tacrolimus also have shown some effectiveness in treating acute refractory rejection in several small series.4 A more recent approach involves the use of daclizumab, a monoclonal antibody directed against the interleukin-2 receptor, in the immediate post-trans-
Villanueva and Garrity
1015
plantation period to prevent acute rejection without the use of anti-lymphocyte globulin.10 REFERENCES 1. Peters SG, McDougall JC, Scott JP, et al. Lung transplantation: selection of patients and analysis of outcome. Mayo Clin Proc 1997;72:85– 8. 2. Boehler A, Estenne M. Obliterative bronchiolitis after lung transplantation. Curr Opin Pulm Med 2000;6:133–9. 3. Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest 1998; 114:1411–26. 4. Garone S, Ross DJ. Bronchiolitis obliterans syndrome. Curr Opin Organ Transplant 1999;4:254 – 63. 5. Paradis I. Bronchiolitis obliterans: pathogenesis, prevention, and management. Am J Med Sci 1998;315:161–78. 6. Cooper J, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts: International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713– 6. 7. Heng D, Phil M, Sharples LD, et al. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant 1998;17:1255– 63. 8. Husain AN, Siddiqui MT, Holmes EW, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Crit Care Med 1999;159:829 –33. 9. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997;155:789 – 818. 10. Garrity ER, Villanueva J, Bhorade S. Low rate of acute lung allograft rejection after the use of Daclizumab, an Interleukin 2 receptor antibody. Transplantation 2000 (In press).
To participate in the management of this case, go to: www.ImmunologyEd.com