Nine years after receiving a bone marrow transplant for aplastic anemia, a 14-year-old girl with severe pulmonary disease associated with graft-versus-host disease received a double lung transplant. Subsequent to lung transplant, her lung function improved dramatically ([FEV.sub.1] increasing from 20 to 73 percent predicted normal, residual volume decreasing from 316 to 130 percent predicted normal values). The patient is currently well 15 months after transplant, while receiving immunosuppression consisting of FK506 and azathioprine. Double lung transplantation may offer a therapeutic option for the treatment of graft-versus-host pulmonary disease in selected patients.
Lung transplantation has become an accepted form of therapy for end-stage pulmonary disease in adults and children. Pediatric patients have undergone lung transplantation for a variety of disease, including cystic fibrosis, idiopathic pulmonary fibrosis, primary pulmonary hypertension, and congenital heart disease.[2-4]
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Bone marrow transplantation (BMT) has been used for a variety of hematologic disorder, including aplastic anemia, acute and chronic leukemias, and immunodeficiencies.[5,6] Graft-versus-host disease (GVHD) is a complication of BMT in 40 to 60 percent of transplant recipients.[7,8] Pulmonary interstitial fibrosis has been found in 20 percent of patients within 12 months after BMT.[7,8] Airway obstruction, especially obliterative bronchiolitis, has been reported in 11 to 17 percent of BMT patients, with chronic GVHD preceding almost all of the cases reported. This pulmonary involvement by GVHD carries a mortality rate of approximately 50 percent. Medical therapy using increased immunosuppression with corticosteroids, antithymocyte globulin, nonspecific [gamma]-globulin, cyclosporine, or FK506 offers promise, but also is associated with substantial toxic reactions and treatment failure. Therefore, alternative therapies for severe pulmonary disease following GVHD are needed. Calhoon et al reported successful single lung transplantation in an adult with pulmonary fibrosis after BMT. We now report lung transplantation as treatment in a child with severe pulmonary GVHD.
A 14-year-old white girl was initially referred to our institution for evaluation for lung transplantation in 1990. Eight years before, she had been diagnosed as having aplastic anemia and received an HLA identical, mixed lymphocyte culture compatible BMT from her sister. Prior to BMT, she received a combination of oral thioguanine and intravenous cytarabine and cyclophosphamide as immunosuppression. Complete engraftment took place by the 14th day after BMT, and long-term immunosuppression was continued with oral azathioprine. Acute GVHD developed 2 weeks after BMT and she was treated with a course of methylprednisolone. Her clinical course was complicated by adenoviral pneumonia 2 months after BMT with the development of respiratory failure requiring mechanical ventilation and tracheostomy 4 months after BMT. Her subsequent course was further complicated by pneumococcal and staphylococcal sepsis treated successfully with intravenous antibiotics.
Over the next 3 years, she developed dyspnea, orthopnea, wheezing, peripheral cyanosis, and exercise intolerance. Pulmonary function testing 3-1/2 years after BMT showed an FVC less than 30 percent of predicted and an oxyhemoglobin saturation of 90 percent during exercise (Table 1). Pulmonary function testing 3 months later indicated a mixed restrictive and obstructive defect. Her chest radiographs showed increased interstitial markings and an echocardiogram 9 years after BMT was consistent with pulmonary hypertension. She was treated with nitroglycerin and supplemental oxygen. Despite these measures, she remained debilitated with chronic cough and exercise limitation.
At the time of referral to our center for lung transplant evaluation, the physical examination revealed a well-nourished girl with moderate dyspnea and a respiratory rate of 36 breaths/min. The thorax had a normal anteroposterior diameter and there were intercostal retractions. Inspiratory and expiratory crackles and an occasional wheeze were heard on auscultation. Cardiac examination revealed a normal [S.sub.1] and a prominent split of [S.sub.2]. There was 2+ clubbing of the digits. A complete blood cell count was normal. Echocardiography demonstrated a mildly dilated right ventricle without tricuspid regurgitation, a moderately dilated pulmonary artery, and early closure of the pulmonary valve consistent with pulmonary hypertension. The right ventricular ejection fraction by a multiple gated acquisition scan was 35 percent. Chest radiograph revealed a right upper lobe bulla as well as emphysematous changes and increased interstitial markings consistent with fibrosis. Pulmonary function testing showed both restriction and very severe obstruction.
She underwent double lung transplant 15 months after the initial evaluation. Pathologic study of her native lungs revealed diffuse interstitial and focal parenchymal fibrosis (with compensatory emphysema) as well as bronchiolitis obliterans, consistent with GVHD of the lung.
Following the transplant, her immunosuppressive regimen included FK506, azathioprine, and prednisone. Episodes of acute cellular rejection were diagnosed by transbronchial biopsy specimens on the ninth and 21st postoperative days. Both of these episodes were treated succesfully with 3-day courses of methylprednisolone. She was discharged from the hospital 1 month after transplant on a regimen of FK506, azathioprine, prednisone, acyclovir, and trimethoprim-sulfamethoxazole.
The patient has done well in the 15 months since hospital discharge and is currently in school without limitation. Results of pulmonary function tests performed 15 months after transplant (Table 1) were virtually normal.
Within the past decade, lung transplantation has become a therapeutic option for the treatment of end-stage pulmonary disease in adults and children.[2-4] Pulmonary GVHD following BMT has been a common and serious problem, often with an inexorable downhill course, despite dramatic medical treatment.
Calhoon et al recently reported the case of an adult who receied a single lung transplant because of severe pulmonary fibrosis following allogeneic BMT. We present a patient who received a BMT for aplastic anemia and then developed a decline in her pulmonary function over the ensuing 4 years. She eventually was left with severe restrictive and obstructive pulmonary disease with a long-term oxygen requirement and exercise intolerance. She has done well in her 15 months following double lung transplantation.
We believe that this case demonstrates the potential efficacy of lung transplantation in children for the treatment of severe pulmonary disease associated with chronic GVHD. Double lung transplantation may offer a therapeutic option for the treatment of GVHD.
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