A 27-year-old woman in third remission of acute myeloid leukemia received allo-HSCT from a 6/8 human-leukocyte-antigen- (HLA-) matched unrelated donor (HLA-C and HLA-DR mismatch) in 1999. X-ray and computed tomography (CT) of the chest and pulmonary flow test (PFT) before allo-HSCT did not reveal any abnormalities. She was not a smoker. The conditioning regimen consisted of 6-fractionated 12
Gy total body irradiation and 120
mg/kg cyclophosphamide. Cyclosporine A (CyA) and short-term methotrexate were used as a GVHD prophylaxis.
Acute GVHD of the skin was observed on day 14. Because it extended rapidly throughout the whole body, oral predonisolone (PSL) at 1
mg/kg was started. While tapering the PSL dose, chronic GVHD of the skin developed in a quiescent manner, and, thus, low-dose of PSL was continued until day 287. She then complained of dry cough and dyspnea on day 295. Serum fungal antigens and cytomegalovirus (CMV) pp65 antigenemia assay were negative. X-ray and HRCT analysis did not reveal any abnormalities. PFT indicated mild restrictive pulmonary dysfunction (FEV1.0%, 98.6%; %VC, 68.1%). Transbronchial lung biopsy (TBLB) showed mild narrowing of bronchioles and alveolar destruction with infiltration of lymphocytes in bronchial walls. There were no fibrotic lesions or severe obliteration of bronchioles (). According to the clinical course and pathological findings, we tentatively diagnosed as early stage of BO after allo-HSCT.
Figure 2 Pathological findings of the TBLB and autopsy. In the TBLB specimens, Victoria blue staining shows the narrowing of bronchioles (a-i) with infiltration of lymphocytes in bronchial walls. There are no fibrotic lesions (a-ii). In the lung tissue at autopsy, (more ...)
Although, oral PSL therapy at 1
mg/kg was resumed, her dyspnea was unchanged.
At the period around day 480 while tapering PSL, her dyspnea worsened. PFT showed moderate to severe obstructive pulmonary dysfunction with restrictive dysfunction (FEV1.0%, 60.1%; %VC, 69.6%; ), compatible with typical BO. After the steroid pulse therapy, oral tacrolimus with PSL at 1
mg/kg was started. Although low-dose oral PSL and tacrolimus were continued, respiratory function was gradually deteriorated until day 3,000 (). She refused the lung transplantation. Because of chronic renal dysfunction, oral tacrolimus therapy was discontinued on day 3300. On day 3600, she fell off the stairs in the house, which caused traumatic pneumothorax and died.
Figure 1 Clinical course and the results of PFT. The solid line and the dotted lines show DLCO, FEV1.0%, and %VC. () The time point that diagnosis of BO was made according to the result of PFT. CyA, cyclosporine A; FK506, tacrolimus; Allo-HSCT, allogeneic (more ...)
An autopsy revealed that there was extensive obliteration or disappearance of bronchioles (Figures and ). Residual bronchioles showed luminal narrowing due to submucosal collagen deposition and smooth muscle hypertrophy of bronchiolar walls (). These findings were compatible with those at the end stage of BO [2
]. Infiltration of lymphocytes in collagen layer with mild luminal narrowing, which was reminiscent of the findings observed in TBLB at the early stage, was also observed in some bronchial lumens (). There were no pathological findings of infection. These observations suggested that the destruction of bronchiole was still progressive even 10 years after diagnosis.