Increased exhaled nitric oxide in bronchiolitis obliterans organizing pneumonia after allogeneic bone marrow transplantation.

Abstract

Recently, exhaled nitric oxide (eNO) was recognized as a noninvasive marker of lung inflammation (1). Bronchiolitis obliterans organizing pneumonia (BOOP) is characterized by a histologic finding of bronchiolitis with granulation tissue in small airways, in alveolar ducts and some alveoli, and in the area of organizing pneumonia (2). Idiopathic BOOP after allogeneic bone marrow transplantation (BMT) is thought to be a noninfectious lung complication and an association of chronic graft-versus-host disease (GVHD), although the etiology is still unknown. We found increased eNO concentration and improvement with immunosuppressive therapy in three patients in whom idiopathic BOOP developed after allogeneic BMT. The time course of eNO levels after the onset of BOOP is shown in Figure 1.Figure 1: Time course of eNO levels after treatment with prednisolone for BOOP. Exhaled NO level was measured according to the recommendation of the European Respiratory Society (9), with a minor modification; exhalation flow rate of 60 mL/sec.Case 1. A 19-year-old male with chronic myelogenous leukemia received a BMT from his HLA-identical sister in November 1997. The conditioning regimen consisted of fractionated total body irradiation (TBI), etoposide, and cyclophosphamide (CY). Short-term methotrexate and cyclosporine were given to prevent GVHD. Engraftment of bone marrow was favorable. After tapering of cyclosporine, the patient complained of nonproductive cough and low-grade fever on day 150. Chest radiograph revealed multiple patchy infiltrates with air bronchogram. High-resolution computed tomography (CT) of the lung demonstrated bilateral nodular patchy inclusions. Lung function tests showed a moderately restrictive impairment. Transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) were performed on day 245. Pathologic findings showed typical features of BOOP. Cytology of BAL fluid revealed a high lymphocyte count (36.0%). Examination of BAL fluid for bacteria, fungi, Pneumocystis, and viruses including cytomegalovirus was negative. The eNO level was 51 parts per billion (ppb) (normal control is 12.9±3.8 [SD] ppb) at the onset of BOOP. He received prednisolone (PSL) at a dose of 1 mg/kg daily. Clinical symptoms disappeared, and the lung lesion mainly improved on CT scan within a month. The eNO level decreased to 13 ppb on day 288. Case 2. A 39-year-old male with chronic myelogenous leukemia underwent a BMT from his HLA-matched sister in November 1998. Conditioning consisted of TBI, cytarabine, and CY. GVHD prophylaxis was identical to case 1. He developed chronic GVHD and has been treated with 10 mg of PSL. He complained of dyspnea and fever on day 667. The results of CT of the lung and TBLB were compatible with BOOP. The cytology of BAL fluid indicated an eosinophil count of 6% and lymphocyte count of 7%. The eNO level showed 52 ppb on day 681. After 1 mg/kg PSL was given, the level of eNO improved to the normal range, with disappearance of clinical findings. Case 3. A 43-year-old male with acute myelogenous leukemia in remission received an HLA-matched unrelated donor BMT in September 2000. The conditioning with TBI and thiotepa and the CY and GVHD prophylaxis was the same as in the above cases. BOOP developed on day 144. The findings of CT scan and TBLB were consistent with BOOP. The BAL fluid indicated a lymphocytosis of 85%. The eNO slightly increased to 18 ppb at this point. He had two recurrences of BOOP, despite treatment with PSL. The level of eNO was 36 ppb at the second recurrence on day 336. After administration of high-dose methyl prednisolone, BOOP was improved, with normalization of eNO level. NO is synthesized from l-arginine in many cells of the respiratory tract by NO synthases. Inducible NO synthase is especially capable of producing large amounts of NO in response to proinflammatory cytokines such as interleukin 1 and tumor necrosis factor-α (3). In a murine BMT model of idiopathic pulmonary syndrome, it has been described that alloreactive T cells activate host alveolar macrophages to release NO and increased NO levels are associated with lung dysfunction (4). BMT-related BOOP usually develops as a late-onset noninfectious pulmonary complication and is often connected with chronic GVHD (5). Therefore, it is speculated that an immune-mediated mechanism and tissue-damaging NO may contribute to the onset and clinical future of BOOP. In previous studies, a significant correlation has been observed between the levels of serum nitrite/nitrate and host-versus-graft and graft-versus-host reactions in rat (6) and human (7,8) BMT. In consideration of these findings, increased eNO production in our cases also suggests that BMT-related BOOP may be a manifestation of chronic GVHD. Although the pathogenesis of BOOP is probably multifactorial and the physiologic role of NO in this pulmonary complication should be resolved, we believe the eNO measurement is a useful monitor for an inflammatory complication such as BOOP after BMT. Heiwa Kanamori1 2 Shin Fujisawa1 Takahiro Tsuburai1 Satoshi Yamaji1 Naoto Tomita1 Katsumichi Fujimaki1 Akira Miyashita1 Shunsuke Suzuki1 Yoshiaki Ishigatsubo1