Published online August 31, 2005
PEDIATRICS
Vol. 116
No. 3
September 2005, pp.
767-770
(doi:10.1542/peds.2005-0806)
Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant Patient With Tumor Necrosis Factor-
Blockade
Jason J. Fullmer, MD*,
Leland L. Fan, MD*,
Megan K. Dishop, MD
,
Cheryl Rodgers, RNP
and
Robert Krance, MD
* Pulmonary Medicine
Pathology
Hematology and Oncology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas
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ABSTRACT
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Bronchiolitis obliterans (BO) in children is a rare, inflammatory/fibrosing process involving the small airways that often results in progressive, irreversible obstructive pulmonary disease. Because treatment has focused mainly on supportive care and generally unsuccessful immunosuppression, children with BO experience significant morbidity and mortality. We report a case of biopsy-proven BO after bone marrow transplantation in a child who, after failed corticosteroid therapy, was treated with infliximab, a monoclonal antibody with binding specificity for human tumor necrosis factor-
. With initiation of treatment, her pulmonary symptoms and radiographic and spirometric evidence of BO resolved. Nine months later, she remains asymptomatic and shows no evidence of pulmonary decompensation. This case illustrates a successful treatment of BO with selective tumor necrosis factor- blockade.
Key Words: bone marrow transplant • bronchiolitis obliterans • tumor necrosis factor-alpha
Abbreviations: BO, bronchiolitis obliterans • BMT, bone marrow transplantation • TNF-, tumor necrosis factor- • GVHD, graft-versus-host disease • HRCT, high-resolution computed tomography • IVIG, intravenous immunoglobulin • RSV, respiratory syncytial virus • FEV1, forced expiratory volume in 1 second • IL, interleukin
Bronchiolitis obliterans (BO), also known as constrictive bronchiolitis or obliterative bronchiolitis, is a rare pulmonary disorder characterized histologically by an inflammatory/fibrosing process that constricts and ultimately obliterates the small airways.1 The functional loss of these airways results in the insidious development of chronic cough and prolonged wheeze, often progressing to severe respiratory distress. Known causes of BO include infection (the most common cause in children), particularly with adenovirus and Mycoplasma; chronic aspiration; toxic fume inhalation; and drugs. BO is also a well-described complication in allograft recipients undergoing lung, heart-lung, and bone marrow transplantation (BMT) and in patients with Stevens-Johnson syndrome.1,2
Children with BO have a highly variable prognosis, with significant long-term morbidity reported in 78% to 92% of patients, depending on the etiology of the initial insult.3,4 Therapeutic interventions in patients developing severe BO have generally been disappointing, and treatment rests primarily on supportive care. Although anti-inflammatory therapy such as corticosteroids, chloroquine, and hydroxychloroquine has been tried in small clinical trials and case reports4–6 in an attempt to modify the disease before fibrosis develops, this approach has met with minimal success. The rarity of BO in children makes prospective, randomized, controlled trials difficult. Thus, it is almost impossible to discern the true therapeutic value of established immunosuppressive agents such as corticosteroids and very difficult to investigate new therapeutic options.
Studies investigating the molecular signaling important in the development of the fibroproliferative stage of BO in both animal models and human subjects have implicated several pro-fibrotic growth factors. One of these, tumor necrosis factor- (TNF-), a mesenchymal growth factor that is known to participate in matrix remodeling, has been shown to be elevated in the early stage of BO in human and animal studies.7,8 Recent studies in experimental mammalian models of BO, and models of graft-versus-host disease (GVHD) with acute lung injury, have shown that blockade of TNF- using a TNF--soluble receptor (TNFR:Fc) significantly reduced epithelial injury and lumenal obstruction.7,9 We present a case of developing, biopsy-proven BO after BMT that was treated with infliximab, a monoclonal antibody with binding specificity for TNF-, after failed corticosteroid therapy. She responded symptomatically and showed reversal of airway obstruction and improvement in lung high-resolution computed tomography (HRCT) findings.
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CASE REPORT
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A previously healthy, 8-year-old Hispanic girl developed severe aplastic anemia with markedly hypocellular bone marrow (<5% cellularity) and cytogenetic evidence of a t(9;22) translocation (BCR-ABL fusion product in 11% of cells). She subsequently underwent matched, unrelated BMT. Her course was complicated by grade I GVHD with skin stage II. She was treated with tacrolimus, intravenous immunoglobulin (IVIG), and corticosteroids. She has remained on tacrolimus and IVIG throughout the course described in this case report. Two months after BMT, she was hospitalized for 5 days with a respiratory syncytial virus (RSV) infection of the lower respiratory tract and treated with ribavirin. During and after this illness, she developed persistent, productive cough, which was evaluated 2 months post-BMT. Compared with previously normal spirometry, her forced expiratory volume in 1 second (FEV1) decreased by 11% to 85% predicted, and her forced expiratory flow, midexpiratory phase, decreased by 50% to 64% predicted, with no response to bronchodilators. Chest radiograph was unremarkable, and an HRCT scan of the chest showed no bronchiectasis or air trapping. She was given a 2-week trial of inhaled steroids and bronchodilators, with no improvement in her symptoms.
Four months after BMT, she was referred to a pulmonary clinic, at which physical examination showed bilateral crackles and wheezing. Repeat pulmonary-function tests showed that her FEV1 had decreased to 57% predicted. A flexible bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies were performed. Copious mucopurulent secretions were present in both lungs. Her bronchoalveolar lavage grew Penicillium sp., for which she was given 2 weeks of amphotericin B. Transbronchial biopsies showed acute bronchitis and bronchiolitis, with focally increased peribronchiolar fibrosis. She was started empirically on oral prednisone (15 mg, twice daily). With this therapy, her FEV1 increased to 87% predicted (Fig 1), and her cough improved but did not completely resolve.
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Fig 1. Pulmonary function: trend of forced vital capacity (FVC) and FEV1, represented as percent predicted (pred), showing response to therapy.
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Approximately 5 months post-BMT, she again developed increased cough and rhinorrhea and worsening fatigue. A nasal swab grew adenovirus at this time. Her symptoms progressed, and her spirometry showed worsening obstruction despite increasing her prednisone to 30 mg, twice daily. A repeat HRCT showed diffuse bronchiectasis, pulmonary nodules, and mosaic lung attenuation (Fig 2). A thoracoscopic lung biopsy showed bronchiolectasis with acute and chronic airway inflammation, constrictive submucosal fibrosis with mucus stasis, and hyperinflation, consistent with obliterative bronchiolitis (Fig 3). Organizing pneumonia and arterial intimal proliferation were also present focally. Special stains and cultures for RSV and adenovirus were negative, as were cultures of the tissue for bacterial, fungal, and acid-fast organisms.
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Fig 2. Expiratory HRCT of chest. The preinfliximab image taken 5 months post-BMT shows hyperinflation, slight mosaic perfusion, small pulmonary nodules, and central bronchiectasis. The postinfliximab image was taken 1 month after initiating infliximab therapy and demonstrates that these abnormalities resolved.
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Fig 3. Thoracoscopic lung biopsy. The biopsy showed varying phases of airway injury typical of obliterative bronchiolitis syndrome. Some bronchioles were ectatic and cellular with an active predominantly lymphocytic inflammatory infiltrate in the mucosa and surrounding the airways (A; right middle lobe, hematoxylin/eosin), whereas others showed less cellularity but early subepithelial fibrosis. The most severely affected airways showed sparse cellularity and near-complete obliteration of the lumen by organized subepithelial fibrosis (B; right lower lobe, Movat Pentachrome).
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Initially, her BO was treated with prednisone (60 mg, twice daily). However, because of a poor clinical response to corticosteroids, she was started on infliximab (10 mg/kg intravenously, twice a week for 4 doses, then weekly for 4 doses, then tapered to every other week for 2 months). She improved clinically, with an increase in her energy level and resolution of her cough, crackles, and wheezing on examination. One month after initiation of infliximab, a repeat HRCT showed resolution of the bronchiectasis, pulmonary nodules, and mosaic attenuation seen previously (Fig 2). Spirometry showed an FEV1 of 108% predicted. At the time of this case report, she had been followed for 9 months. She remained asymptomatic with normal pulmonary function and has been weaned from her oral corticosteroids.
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DISCUSSION
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BO is a rare complication of airway epithelial injury in children. As stated previously, the initial insult is typically of an infectious, chemical, or immunologic nature. With progressive airway obstruction, these patients develop hyperinflation with areas of atelectasis, impaired mobilization of secretions, and the development of bronchiectasis and fibrosis. The clinical spectrum is heterogenous and can vary from only exercise-related symptoms to progressive respiratory failure. Commonly there is persistence of respiratory symptoms (cough and wheeze) and signs (tachypnea, crackles, and wheezes on auscultation) beyond the expected time frame after pulmonary injury.2
Chronic airflow obstruction from BO is the most common late complication of BMT, typically occurring beyond the third month.3 The incidence in allogenic populations varies between 6% and 26% in published series.10,11 The patient highlighted in this case report had typical risk factors for developing BO. Chronic, low-grade GVHD has been implicated as a risk factor for the development of BO in patients having BMT.3 Recurrent viral infection has been identified as another risk factor for development of BO post-BMT.10 There is evidence that both GVHD and infection may act in synergy to produce BO. This patient was diagnosed with both GVHD and RSV and adenoviral infections within the first 100 days post-BMT. The timing and nature of her clinical symptoms, combined with worsening obstruction on lung-function testing and HRCT changes, were characteristic for BO. However, given the broad differential diagnosis for chronic respiratory symptoms in an immunosuppressed host, the decision was made to pursue a definitive diagnosis by thoracoscopic lung biopsy. Her biopsy showed typical features of evolving BO with no evidence of any infectious source or alternative pulmonary pathology.
The pathogenesis of BO has been studied extensively in the posttransplant population of patients and to a lesser degree in nontransplant cases. Regardless of the initiating event, the basic mechanisms behind the development of BO seem similar. Bronchiolar epithelial cells are damaged, and T lymphocytes and neutrophils are recruited to the site of injury. Vast arrays of cytokine and chemokine networks (those implicated include TNF-, interleukin 2 [IL-2], interferon 
, IL-8, RANTES [regulated on activation, normal T-cell expressed and secreted], platelet-derived growth factor, transforming growth factor, and fibroblast growth factor)7,12,13 are activated, perpetuating an inflammatory response. With repeated or persistent inflammation, there is an exaggerated fibroblastic response leading to peribronchiolar fibrosis and obliteration of the airways. Furthermore, genetic polymorphisms have been described that may infer increased susceptibility to the development of BO.14
As stated previously, therapeutic interventions have focused on the suppression of the inflammatory response in BO. In general, current immunosuppressive regimens have been ineffective in controlling disease progression. Given the rarity of this disease, randomized, controlled therapeutic trials have been impossible to perform. As a result, the ideal timing, dosage, or choice of immunosuppressive agent is unknown. Although multiple cytokines and chemokines have been identified in the pathogenesis of BO, TNF- seems to play a central role in the inflammatory reaction and enhanced fibroblast proliferation. Furthermore, with the recent findings from animal models of BO and of GVHD with acute lung injury, showing reduced inflammation, fibrosis, and luminal obstruction with TNF- blockage,7,9,15 and the commercial availability of anti-TNF- antibodies (infliximab, etanercept, and adalimumab), there is a rationale for the use of TNF- blockade in the treatment of developing BO.
Infliximab is a monoclonal, chimeric antibody composed of a murine antigen-binding region joined to the human IgG1 constant region, with binding specificity for human TNF-.16 Infliximab is approved by the Food and Drug Administration for treatment of rheumatoid arthritis and Crohn's disease. Its use has also been reported in the treatment of other inflammatory diseases including sarcoidosis, ankylosing spondylitis, psoriasis, and the gastrointestinal manifestations of GVHD.16,17 Infliximab is generally well tolerated, but there are associated adverse effects, including increased susceptibility to mycobacterial infections.18
The patient presented here demonstrated progressive airway obstruction despite the use of systemic corticosteroids. Infliximab was initiated based on data suggesting a role for TNF- in the development of BO and studies suggesting the safety of its use in patients having BMT.17 She seemed to respond remarkably well to therapy, with cessation of her cough, resolution of obstructive lung disease via spirometry, and improvement in her HRCT findings. It is unlikely that other therapeutic intervention caused this improvement (corticosteroids, IVIG, tacrolimus, and prior amphotericin B), because these therapies were begun well before infliximab therapy, and her lung disease continued to progress until infliximab was initiated.
One weakness of this report is that TNF- levels were not measured to confirm an elevation in this proinflammatory cytokine. Elevated TNF-, IL-6, and IL-8 have been associated with poorer prognosis in postadenoviral BO.8 Thus, it may be reasonable to measure serum TNF- before initiating therapy with TNF- blockade. However, the measurement of TNF- levels in serum is complex, because much of TNF- is carried by soluble receptors. Therefore, a simple measure of the TNF- level, without measuring both TNF- and its various soluble receptors, may not give one a true measure of the activity of this cytokine.
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CONCLUSIONS
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We report a case of a child who developed BO after BMT with a progressive course despite augmented immunosuppression with corticosteroids. The addition of TNF- blockade with infliximab seemed to resolve her symptoms and airway obstruction in a very dramatic fashion, and she remained symptom free 9 months afterward. Additional investigation is needed to validate the effectiveness of TNF- blockade in the treatment of BO post-BMT. Given the known spectrum of changes in BO from lymphocytic bronchiolitis to organizing and organized phases of subepithelial fibrosis in constrictive and obliterative bronchiolitis, it is likely that the timing of therapy early in the course of disease may predict a greater degree of response. The hypothesis remains to be tested in other patients treated by this approach. If these findings can be confirmed, it still must be determined if patients with BO secondary to other disease processes would benefit.
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FOOTNOTES
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Accepted May 18, 2005.
Address correspondence to Leland L. Fan, MD, Department of Pediatrics, Pulmonology Section, Texas Children's Hospital, 6621 Fannin, CC 1040.00, Houston, TX 77030. E-mail: llfan{at}texaschildrenshospital.org
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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ABSTRACT
CASE REPORT
