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Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant
Patient With Tumor Necrosis Factor- α Blockade
Jason J. Fullmer, Leland L. Fan, Megan K. Dishop, Cheryl Rodgers and Robert
Krance
Pediatrics 2005;116;767
DOI: 10.1542/peds.2005-0806
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2005 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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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§
ABSTRACT. 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. Pediatrics
2005;116:767–770; 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; FEV 1 , 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
*From the Sections of Pulmonary Medicine, ‡Pathology, and §Hematology
and Oncology, Department of Pediatrics, Texas Children’s Hospital and
Baylor College of Medicine, Houston, Texas.
Accepted for publication May 18, 2005.
doi:10.1542/peds.2005-0806
No conflict of interest declared.
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@texaschildrenshospital.org
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Academy
of Pediatrics.
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 reports 4–6 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.
CASE REPORT
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
PEDIATRICS Vol. 116 No. 3 September 2005 767
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the lower respiratory tract and treated with ribavirin. During and
after this illness, she developed persistent, productive cough, which
was evaluated 2 1 ⁄2 months post-BMT. Compared with previously
normal spirometry, her forced expiratory volume in 1 second (FEV 1 )
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 FEV 1 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 FEV 1 increased to 87% predicted (Fig 1), and her
cough improved but did not completely resolve.
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.
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 FEV 1 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.
DISCUSSION
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 differen-
Fig 1. Pulmonary function: trend of forced vital capacity (FVC) and FEV 1 , represented as percent predicted (pred), showing response to
therapy.
768 TREATMENT OF BRONCHIOLITIS OBLITERANS WITH TNF- BLOCKADE
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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.
A
B
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).
tial 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.
EXPERIENCE AND REASON 769
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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.
CONCLUSIONS
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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770 TREATMENT OF BRONCHIOLITIS OBLITERANS WITH TNF- BLOCKADE
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Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant
Patient With Tumor Necrosis Factor- α Blockade
Jason J. Fullmer, Leland L. Fan, Megan K. Dishop, Cheryl Rodgers and Robert
Krance
Pediatrics 2005;116;767
DOI: 10.1542/peds.2005-0806
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2005 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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