Bronchiolitis obliterans organizing pneumonia and chronic graft

Bone Marrow Transplantation, (1997) 19, 841–844  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Case report Bronchiolitis obliterans organizing pneumonia and chronic graftversus-host disease in a child after allogeneic bone marrow transplantation I Kleinau1, A Perez-Canto2, HJ Schmid3, A Grassot4 , D Staab1, H Renz5 , G Henze3, U Wahn1 and K Paul1 1

Department of Paediatric Pulmonology/Immunology, 3Department of Paediatric Oncology, 5Institute of Clinical Chemistry and Biochemistry, Virchow Klinikum, Humboldt University of Berlin; 2Department of Pathology, Free University of Berlin; and 4 Department of Radiology, Chest Hospital Heckeshorn, Berlin, Germany

Summary: We report an 8-year-old boy who developed cough and respiratory failure 7 months after bone marrow transplantation (BMT) coinciding with the onset of chronic graft-versus-host disease (GVHD). Lung function data, imaging studies, lung biopsy and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia. While this has been reported in association with chronic graft-versus-host disease in one adult case previously, we report the simultaneous occurrence of BOOP and chronic GVHD in a child after bone marrow transplantation for the first time. Keywords: bone marrow transplantation; children; interstitial pneumonia

There has been extensive progress in clinical bone marrow transplantation over the last decade. Long-term relapse-free survival is now a reality for many children, so that late sequelae like pulmonary complications are becoming a significant cause for morbidity and mortality.1 While infectious processes are a major source of these complications in the early post-transplant period, non-infectious pulmonary disorders have been described later, predominantly in patients with chronic graft-versus-host disease (GVHD). Bronchiolitis obliterans organizing pneumonia, also termed cryptogenic organizing pneumonia, is a clinicopathologic syndrome distinct from bronchiolitis obliterans and was first described by Epler et al.2 It occurs following exposure to various infectious agents, inhalation of toxic fumes, as manifestation of connective tissue disease or idiopathically. This entity consists of characteristic histological lesions: bronchiolitis with granulation tissue plugs within the lumen of small airways extending into alveolar Correspondence: Dr K Paul, Department of Pediatric Pulmonology/ Immunology, Virchow Klinikum, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany Received 29 June 1996; accepted 16 December 1996

ducts/alveoli, and areas of organizing pneumonia. In addition, the clinical manifestations of bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia are quite distinct. Patients with bronchiolitis obliterans organizing pneumonia report dyspnoea, and late inspiratory crackles are present on physical examination. They have abnormal gas exchange and show a restrictive lung function pattern. The chest radiograph in bronchiolitis obliterans organizing pneumonia often shows patchy areas of consolidation. In contrast to bronchiolitis obliterans, bronchiolitis obliterans organizing pneumonia has a fair to excellent prognosis on steroid therapy.2 Recently, bronchiolitis obliterans organizing pneumonia has also been reported after bone marrow transplantation.3 Since patients with bronchiolitis obliterans organizing pneumonia usually present with multiple pulmonary infiltrates resembling an infectious process, it may be underrecognized after marrow transplantation. However, if a definitive diagnosis of bronchiolitis obliterans organizing pneumonia can be established, treatment with prednisolone may reduce the morbidity and mortality usually associated with this syndrome. A number of reports indicate an association of chronic GVHD with various pulmonary pathologies such as bronchiolitis obliterans.4–6 While there is one reported adult case with bronchiolitis obliterans organizing pneumonia in connection with chronic GVHD, a previous report about three children with bronchiolitis obliterans organizing pneumonia showed no such association.7,8 We report a child who developed bronchiolitis obliterans organizing pneumonia coinciding with chronic GVHD. Case report The 8-year-old boy with acute lymphoblastic leukaemia in persistent isolated bone marrow relapse after first remission underwent an allogeneic marrow transplantation from his HLA-matched sister in May 1995. Conditioning consisted of total body irradiation to 1200 cGy in six fractions over 3 days and etoposide 60 mg/kg on day 23. For GVHD prophylaxis he received methotrexate 15 mg/m2 body sur-

BOOP and chronic GVHD in a child after BMT I Kleinau et al

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face on day 11 and 10 mg/m2 body surface on day 13, 16 and 111. His initial course was complicated by grade I acute GVHD of the skin on day 120 and by grade II acute GVHD of the gut and liver by day 141 which resolved with methylprednisolone. At the same time a positive cytomegalovirus (CMV)-PCR of peripheral blood revealed a cytomegalovirus infection which was treated with gancyclovir and CMV-specific hyperimmunoglobulin. The patient did well until day 1195 when he presented with a non-productive cough and shortness of breath. Chest examination was unremarkable. A chest X-ray showed some infiltrates in the right hilar region. CMV-PCR of peripheral blood was negative and there was no CMV-antigenemia detectable. He was placed on broad-spectrum antibiotics (TMP/SMZ), but within 3 weeks his respiratory status deteriorated and he needed supplemental oxygen. He also developed a macular eczema starting with the lung disease and skin biopsy showed evidence of chronic GVHD. He was referred to our hospital and presented with dyspnoea at rest. A chest radiograph and lung-CT scan revealed bilateral nodular patchy infiltrates (Figure 1). Lung function testing showed a FEV1 of 0.37 l/min (25% of predicted),9 VC 0.42 l/min (23% of predicted) and TLC of 1.04 l (42% of predicted). Carbon monoxide diffusion capacity was not measured because lung volumes were too small, but a 6 min walk showed a lowered oxygen saturation (79%) after 150 m. Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy were performed. Stains and cultures for fungi, bacteria, Pneumocystis, Mycobacteria and viruses including cytomegalovirus were all negative. Histological and immunohistological evaluation showed small airways which were partially occluded by loose connective tissue (Figure 2a) or filled with granulation tissue (Figure 2b). These findings were associated with extensive interstitial mononuclear infiltrates and focal interstitial fibrosis (Figure 2c) resembling bronchiolitis obliterans organizing pneumonia. Differential cytology and flow cytometry analysis of BAL fluid revealed a high eosinophil count (21%), a lymphocytosis of 10% and an

elevated percentage of HLA-DR1 T cells (60%) with a low CD4/CD4 ratio (0.3). The patient received a methylprednisolone pulse (10 mg/kg i.v. on 3 consecutive days) and was placed on oral steroids 1 mg/kg tapered over the next 2 weeks. He responded within days with clinical and radiological improvement and on re-evaluation 2 weeks after the second i.v. methylprednisolone pulse (4 weeks after the first) he showed improvement of lung function with FEV1 0.6 l/min (41% of predicted), VC 0.6 l/min (32% of predicted) and TLC 1.19 l (48% of predicted). He had normal blood gas values at rest and showed only a slight lowering of oxygen saturation (91%) after a 6 min walk (450 m). The radiological changes had completely resolved (Figure 3). Analysis of the BAL fluid showed 85% macrophages, 12% lymphocytes, 1% eosinophils and 2% neutrophils, but a reduced CD4/CD8 ratio (0.04) with an elevated percentage of HLADR1 T cells (77%). A regimen of i.v. methylprednisolone pulses once every 4 weeks (10 mg/kg on 3 consecutive days) and oral steroids (5 mg/day) given daily was instituted. After 4 months therapy the patient is still doing well. He has a normal lung function now with FEV1 1.32 1 (89% of predicted), VC 1.42 l (77% of predicted) and TLC 1.22 l (49% of predicted). The 12 min walk shows no decrease of oxygen saturation after 950 metres. The BAL cytology reveals normal differential cell counts with a normal CD4/CD8 ratio (0.5) and a normal percentage of HLADR1 T cells (4%).

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b

Discussion Despite encouraging development in bone marrow transplantation, transplant-related complications, especially those involving the lung, have limited its success. Interstitial pneumonias account for more than 40% of transplantrelated deaths and approximately half of these pneumonias are noninfectious idiopathic pneumonias, which have been termed idiopathic pulmonary syndrome since the NHLBI Workshop in Bethesda in 1991.10 Bronchiolitis obliterans

Figure 1 Imaging before therapy: (a) chest radiograph with bilateral patchy infiltrates; (b) lung CT scan with peribronchiolar thickening and marked irregular-shaped infiltrates distributed over all lung zones.


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Figure 3

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Figure 2 (a) Bronchiolus almost completely occluded by loose connective tissue (haematoxylin and eosin, original magnification 3 150). (b) Small bronchiolus filled with cellular granulation tissue with some lymphocytes (haematoxylin and eosin, original magnification 3 200). (c) Bronchiolitis obliterans with severe interstitial pneumonia, narrowing of the alveoli and focal disruption of granulation tissue in small air spaces (PAS, original magnification 3 200).

organizing pneumonia, recently clarified by Epler et al2 as distinct from bronchiolitis obliterans, has previously been reported following bone marrow transplantation. The role of GVHD in the pathogenesis of various pulmonary pathologies after marrow transplantation is still a matter of debate. Since 1982 several manifestations of GVHD of the lung have been reported, including bronchiolitis obliterans, lymphocytic interstitial pneumonitis and pulmonary fibrosis.4,5,11 Thirman et al7 recently reported a first case of bronchiolitis obliterans organizing pneumonia

Imaging after therapy: normal chest radiograph.

in connection with GVHD in an adult patient following bone marrow transplantation, whereas Mathew and colleagues8 could not show any evidence of GVHD in three reported children with bronchiolitis obliterans organizing pneumonia after bone marrow transplantation. Our patient represents the first documented paediatric case with bronchiolitis obliterans organizing pneumonia and chronic GVHD. Since we found no infectious source, the etiology remains unclear. The simultaneous appearance of chronic cutaneous GVHD and clinical signs of bronchiolitis obliterans organizing pneumonia is noteworthy. That the BAL-T lymphocytes consisted mainly of CD81 cells with an increased percentage of HLA-DR1 T cells is of interest. A cytomegalovirus pneumonitis as one possible reason for this finding was excluded by cytology, CMVPCR and culturing of lavage fluid. The proportion of CD81 cells is also frequently increased in patients following BMT irrespective of any pulmonary complication and a reduced CD4/CD8 ratio with an increase in CD81 cells is also found in bronchiolitis obliterans organizing pneumonia. 12,13 Pulmonary GVHD could be another explanation for elevation of activated CD81 T cells, but to our knowledge no specific lymphocyte function test has so far been established to prove this. While the definite pathogenesis of bronchiolitis obliterans organizing pneumonia in marrow transplant patients is not known, its association with GVHD suggests that immunological reactions might play a key role in the development of bronchiolitis obliterans organizing pneumonia in these patients.13 Together with the prompt response to immunosuppression, all these findings indicate bronchiolitis obliterans organizing pneumonia as a possible pulmonary manifestation of chronic GVHD in this child. There are three possible explanations for the high eosinophil count in the first BAL fluid without a peripheral blood eosinophilia in our patient. One explanation could be a drug reaction, because the child had recently been treated with sulphonamides, which are known to cause pulmonary eosinophilia. A second possibility could be the diagnosis of chronic eosinophilic pneumonia, but this was excluded by histological evaluation. This leaves the bronchiolitis obliterans organizing pneumonia, which has repeatedly


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been associated with BAL eosinophilia13 as a likely explanation for the high eosinophil count in the first BAL. For early diagnosis of pulmonary complications in asymptomatic patients after BMT, it is necessary to perform a non-invasive pulmonary follow-up programme consisting of regular lung function measurements, capillary blood gas analysis at rest, monitoring of the oxygen saturation after exercise (6 min walk) and measurement of respiratory rate at rest. With the onset of clinical signs of pulmonary complications, further diagnostic procedures including chest radiograph, CT scan, bronchoalveolar lavage and if necessary a transbronchial or open lung biopsy should be performed. Bronchoalveolar lavage has been established as a diagnostic tool in the setting of bone marrow transplantation and it has been postulated that sequential bronchoalveolar lavages at defined times before and after marrow transplantation are indicated for intra-individual comparison of various parameters in order to predict consecutive lung disease in asymptomatic patients.13 Since timely treatment with immunosuppressive agents will reduce the morbidity and mortality of bronchiolitis obliterans organizing pneumonia, early screening for this condition by the diagnostic programme mentioned above is mandatory after bone marrow transplantation.14 References 1 Link H, Ostendorf P, Wernet P et al. Pulmonary complications after allogeneic bone marrow transplantation – the Tubingen experience. Exp Hematol 1982; 12 (Suppl. 15): 21–22. 2 Epler GR, Colby TV, McCloud TC et al. Bronchiolitis obliterans organizing pneumonia. New Engl J Med 1985; 312: 152–158. 3 Cordier JF, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia: definition of characteristic clinical profiles in a series of 16 patients. Chest 1989; 96: 999–1003.

4 Roca J, Granena A, Rodriguez-Roisin R et al. Fatal airway disease in an adult with chronic graft-versus-host disease. Thorax 1982; 37: 77–78. 5 Perrault C, Cousineau S, D’Angelo G et al. Lymphoid interstitial pneumonia after allogeneic bone marrow transplantation. Cancer 1985; 55: 1–9. 6 Raschko JW, Cottler-Fox M, Abbondanzo SL et al. Pulmonary fibrosis after bone marrow transplantation responsive to treatment with prednisone and cyclosporine. Bone Marrow Transplant 1989; 4: 201–205. 7 Thirman MJ, Devine SM, O’Toole K et al. Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 10: 307–311. 8 Mathew P, Boman P, Krance RA et al. Bronchiolitis obliterans organizing pneumonia (BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994; 13: 221–223. 9 Knudson RJ, Lewitz MD, Holberg CJ et al. Changes in the flow volume curve with growth and aging. Am Rev Respir Dis 1983; 123: 659–664. 10 Clark JG, Hansen JA, Hertz MI et al. Idiopathic pulmonary syndrome after bone marrow transplantation. NHLBI Workshop Summary. Am Rev Respir Dis 1993; 147: 1601–1606. 11 Atkinson K, Turner J, Biggs JC et al. An acute pulmonary syndrome possibly representing acute graft-versus-host disease involving lung interstitium. Bone Marrow Transplant 1991; 8: 231–234. 12 Leskinen R, Taskinen E, Volin L et al. Use of bronchoalveolar lavage cytology and determination of protein contents in pulmonary complications of bone marrow transplant recipients. Bone Marrow Transplant 1990; 5: 241–245. 13 Quabeck K. The lung as a critical organ in marrow transplantation. Bone Marrow Transplant 1994; 14 (Suppl. 4): S19– S28. 14 Nizami IY, Kissner DG, Visscher DW, Dubay BA. Idiopathic bronchiolitis obliterans with organizing pneumonia. An acute and life-threatening syndrome. Chest 1995; 108: 271–277.