Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and ...
Bone Marrow Transplantation (2000) 26, 907–910 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt
Case report Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin T Ishii1,2, A Manabe1, Y Ebihara1, T Ueda1, H Yoshino1, T Mitsui1, H Hisakawa1, H Yagasaki1, A Kikuchi1, T Yoshimasu1, R Tanaka1, T Takahashi3, A Masunaga4, K-I Sugita5, T Nakahata1, S Asano1,2 and K Tsuji1 Departments of 1Pediatric Hematology-Oncology, 2Cell Transfusion, 3Infectious Disease, 4Pathology, Institute of Medical Science, The University of Tokyo, Tokyo; and 5Department of Pediatrics, Dokkyo Medical School, Tochigi, Japan
Summary: We report a 13-year-old boy who developed dyspnea at rest 1 year after the occurrence of cGVHD following an allogeneic bone marrow transplant (BMT). Pulmonary function data, imaging studies, lung biopsy, and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). Although reports suggest that oral methylprednisolone or methylprednisolone pulse therapies improve BOOP after BMT, we treated our patient with a combination of oral prednisolone (1 mg/kg) and low dose erythromycin (10 mg/kg) to avoid the side-effects of high-dose steroids. With this therapy, our patient showed clinical and radiological improvements within 1 week. The steroids were tapered off 12 months later and erythromycin was given for 14 months. We conclude that therapy consisting of a combination of oral prednisolone and lowdose erythromycin for BOOP after BMT may minimize the dose and duration of steroid use. Bone Marrow Transplantation (2000) 26, 907–910. Keywords: bone marrow transplantation; BOOP; chronic GVHD; erythromycin
Outcome after bone marrow transplant (BMT) has shown a slow but significant improvement over the past two decades. Increased survival is mainly attributable to advances in the management of transplant-related complications through more effective immunosuppressive therapy, antiviral drugs, and more stringently tested blood products. Pulmonary complications of BMT are diverse and account for significant morbidity and mortality. More than 30% of transplant-related deaths are attributable to respiratory disorders.1–5 The major factors contributing to the occurrence of pulmonary disease are immunosuppression, common and Correspondence: Dr K Tsuji, Department of Pediatric HematologyOncology, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, Japan Received 13 March 2000; accepted 24 July 2000
rare infections, the irradiation and chemotherapy used prior to and after BMT, and acute and chronic graft-versus-host disease (GVHD). Bronchiolitis obliterans organizing pneumonia (BOOP) is a respiratory disorder characterized by a restrictive ventilatory pattern and multiple confluent shadows on chest radiographs. Corticosteroids are effective, although the total doses of steroids are usually high and tend to result in adverse effects, such as immunosuppression, osteoporosis, and growth retardation, especially in children. Based on the report of successful treatment of idiopathic BOOP with single agent erythromycin,6 we employed a combination of steroids and erythromycin in an attempt to reduce the total dose and duration of steroids in a child with BOOP after BMT. This combination may be an option for the treatment of BOOP in children. Case report A 13-year-old boy with aplastic anemia received a genotypically HLA-identical BMT from his sister in August 1995. Conditioning consisted of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. GVHD prophylaxis was with short-term methotrexate (MTX) and cyclosporine (CYA). Graft failure occurred and a second BMT from the same donor was given in February 1996 employing total body irradiation (TBI) 9 Gy in three fractions and shortterm MTX and CYA for GVHD prophylaxis in February 1996. The post-transplant clinical course was complicated by grade I acute GVHD of the gut on day 10, which resolved with methylprednisolone. The patient also developed chronic GVHD with skin rash, involvement of the buccal mucosae and liver dysfunction, which started on day 420 after the second BMT. The severity of chronic GVHD was assessed as the limited type. He was treated with steroids and CYA. In November 1997, when he was taking only CYA, dyspnea during vigorous exercise developed and his pulmonary function progressively worsened. He was admitted to our hospital with dyspnea at rest in March 1998, 1 year after the chronic GVHD began. Chest
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X-ray and lung-CT scans revealed bilateral nodular patchy infiltrates (Figure 1). Lung function tests showed VC 2.47 l (90.8% of predicted), FEV1.0% (FEV1.0/FVC) of 92.5%, TLC of 3.41 l, and DLCO of 14.05 ml/min/mmHg (56.5% of predicted). Arterial blood gas analysis showed 43.8 mmHg of pCO2 and 93.2 mmHg of pO2. Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy was performed. Stains and cultures for fungus, bacteria, and the polymerase chain reaction (PCR) for Mycobacterium tuberculosis, Pneumocystis, and viruses including cytomegalovirus (CMV) were all negative. Histological evaluation showed myxomatous connective tissue plugs within the lumens of alveoli, swelling of alveolar epithelium, and infiltration of lymphocytes into the alveolar walls and around the bronchioles (Figure 2). Cytology and flow cytometric analysis of BAL fluid revealed lymphocytosis and an elevated percentage of CD8⫹ T cells (83.4%) with a low CD4/CD8 ratio (0.05). Notably, the majority of lymphocytes were CD8⫹CD11b⫺ (72.5%), which is known to be characteristic of BOOP.6 A combination of oral prednisolone 40 mg (1 mg/kg/day) and low-dose erythromycin 400 mg (10 mg/kg/day) was started. The patient responded within 3 days clinically and radiological improvement was documented after 2 weeks (Figure 3). He showed a dramatic improvement in lung function with VC 3.18 l (119.1% of predicted), FEV1.0% of 91.9%, TLC of 4.39 l, and DLCO of 21.86 ml/min/mmHg (89.0% of predicted). The dose of prednisolone was then decreased as follows: 40 mg for 2 weeks, 30 mg for 2 weeks, 25 mg for 3 weeks, 20 mg for 2 weeks, 15 mg for 2 months, 10 mg for 2 months, 5 mg for 4 months, 2.5 mg for 1 month and it was stopped after 1 year from the diagnosis of BOOP. Erythromycin was continued for 14 months
Figure 2 The specimen was taken from the right B9a by transbronchial biopsy. Granulation tissue plugs within lumens of alveoli, the swelling of alveolar epithelium, and the infiltration of lymphocytes into the alveolar walls and around the bronchioles.
and CYA was finally discontinued in July 1999. At the time of this report, in January 2000, the patient had a 100% Karnofsky score and showed no symptoms related to chronic GVHD or BOOP. Discussion Respiratory failure is one of the main causes of death in patients who have undergone bone marrow transplantation. Cough, or an increased respiratory rate are usually the first clinical signs of pulmonary disease in patients who have undergone BMT, and diagnostic measures including aus-
Figure 1 Imaging before therapy: chest X-ray (a) and chest CT scan (b). Bilateral nodular patchy infiltrates and the consolidation shadow in the right lung field are demonstrated. Bone Marrow Transplantation
Erythomycin and steroids for BOOP after BMT T Ishii et al
Figure 3 Chest CT scan 2 weeks after therapy. The levels of the CT sections corresponded to those in Figure 1b.
cultation, blood gas analysis, chest radiography, CT scan, BAL and lung function tests should be performed promptly to define the underlying disorder. Bronchiolitis obliterans (BO) and BOOP are pulmonary disorders which occur after BMT and share clinical symptoms such as cough and dyspnea. Patients with BO leading to progressive respiratory failure present with an obstructive pattern in lung function tests and hyperinflated lungs on chest radiography. On the other hand, BOOP has distinct laboratory findings and it responds to the administration of steroids. On diagnostic imaging, multiple confluent shadows in the lower zones is typically detected in patients with BOOP and bronchi- and bronchiectasis, centrilobular opacities, or a mosaic pattern of lung attenuation is characteristic of BO.7 In the case described here, a CT scan showed nodular, patchy rather than confluent shadows. It
should be noted that the radiological distinction between BOOP and BO may be difficult in some cases. Various immunological, toxic or inflammatory insults to the lung may lead to histopathological lesions consisting of organizing exudates with plugs of granulation and connective tissue in the distal airways, extending into the alveoli. Lymphocytes, plasma cells and also a few granulocytes may be identified in the center of the plugs. The BAL fluid in BOOP is characterized by a high number of lymphocytes, a low CD4/CD8 ratio and a significantly high number of CD8⫹CD11b⫺ cells compared to that seen in healthy volunteers.6 Prednisolone has been used in patients with symptomatic and aggressive BOOP. It is recommended that the dosage should be 60 mg (1 mg/kg) for 1 to 3 months, and that thereafter it should be decreased to 40 mg for 3 months, and 10 to 20 mg daily for a total of 1 year.8 One report described a child with BOOP who was treated with highdose (pulse) methylprednisolone.9 Erythromycin is widely used for acute and chronic respiratory disorders. Ichikawa et al10 reported that low-dose erythromycin without steroids was used in six patients with idiopathic BOOP, and that improvement was seen in all of them. To avoid the side-effects of steroids, we selected a combination of oral prednisolone and low-dose erythromycin for a patient with BOOP occurring after BMT, and the symptoms of BOOP disappeared on radiographs and respiratory tests, and the clinical condition improved rapidly. The total dose of steroids used in this patient was much less than the recommended dose mentioned above although the duration of steroid therapy was similar. The pharmacological mechanism of action of erythromycin in BOOP remains unclear. It has been suggested that the effect of erythromycin be due to more than its antimicrobial activity in patients with diffuse panbronchiolitis. For example, erythromycin reduces bronchial exudates and also impairs the function of neutrophils in bronchiolitis. Ichikawa et al11 demonstrated that the number of neutrophils and the neutrophil-derived elastolytic-like activity in BAL fluids were decreased significantly after treatment with erythromycin along with a significant improvement in pulmonary function studies in patients with diffuse panbronchiolitis. A similar mechanism of action may occur in patients with BOOP although further studies are necessary. In view of the side-effects of high-dose steroid therapy, we recommend the combination of low-dose oral steroids and low-dose erythromycin. Another important point raised by the present case was that BOOP was observed as a very late complication after BMT. Generally, BOOP occurs in association with chronic GVHD.9 However, our patient showed evidence of BOOP more than 2 years after BMT, when chronic GVHD had almost disappeared. We must keep in mind that BOOP may occur when patients have suffered from chronic GVHD for a long time period. In conclusion, we treated BOOP in a child after BMT with a combination of relatively low doses of steroids and erythromycin. Although the role of erythromycin is entirely speculative, this strategy is worth trying in patients with BOOP after BMT, especially in children.
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