Bronchiolitis Obliterans Sy
Hematopoietic Stem Cell Transplantation—An
Increasingly Recognized M
Graft-versus-H
Jason W. Chien,1 Steven Duncan,2 Kirste
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CRC 3-3330, Bethesda, MD 20892 (e-mail: pavletis@mail.nih.
gov).Published
1083-8791
doi:10.101
S106and delay in diagnosis. This article provides a
view of the epidemiology, diagnosis, and tre
of BOS and the immunobiology of BOS aft
transplantation, a better understood disease
to BOS after HSCT pathologically, clinical
radiographically.
EPIDEMIOLOGYAND PATHOGENESIS
rch Center and Pulmonary and Critical Care, University
shington, Seattle, Washington; 2Division of Pulmonary,
y and Critical Care Medicine, University of Pittsburgh
al Center, Pittsburgh, Pennsylvania; and 3Experimental
plantation and Immunology Branch, National Cancer
te, NIH, Bethesda, Maryland.
isclosure: See Acknowledgments on page S112.
dence and reprint requests: Steven Pavletic, MD, Head,
-versus-Host and Autoimmunity Unit, Experimental
plantation and Immunology Branch, National Cancer In-
, Center for Cancer Research, 10 Center Drive, Roomedge about pathogenesis to direct effective therapiesFrom the 1Clinical Research Division, Fred Hutchinson CancerKEY WORDS: Bronchiolitis obliterans, Chronic graft-versus-host, Allogeneic transplantation
DUCTION
significant decrease in early treatment-related
y (TRM) after allogeneic hematopoietic cell
ntation (HSCT) increased the number of pa-
ing long enough to experience late complica-
transplantation. Chronic graft-versus-host
cGVHD) is the most common late complica-
llogeneic HSCT, and when lungs are affected
by cGVHD, bronchiolitis obliterans syndrome
ensues. Unfortunately, the survival and treatm
patients with BOS have not improved over
20 years [1,2]. Attempts at clinical trials hav
hindered by the lack of uniform diagnostic
Recently, the NIH consensus project for cri
cGVHDhasmade recommendations regarding
agnosis of BO and monitoring of lung disease
long-term survivors [3]. Challenges to the p
in medical management of BOS include littleBiol Blood Marrow Transplant 16: S106-S114 (2010) Putherapies for patients with BOS after HSCT.
blished by Elsevier Inc.radiographic presentation, and presumed immunologic pathogenesis. This review describes the current
understanding of the epidemiology and pathogenesis of BOS and presents information on evaluations andoccur following allogeneic hematopoietic stem cell
tion. Current estimates in the literature suggest tha
ients and 6% of patients who develop chronic graft-v
However, based on newer data it is likely that the tru
and treatment of patients with BOS after HSCT has
trials have been hindered by the lack of uniform dia
a reversible stage in its natural history. Recently, the
for criteria in cGVHD has made recommendations
disease among long-term survivors. Although a r
BOS occurs commonly after lung transplantatioby Elsevier Inc.
/10/161S-00018$36.00/0
6/j.bbmt.2009.11.002anifestation of Chronic
ost Disease
n M. Williams,3 Steven Z. Pavletic3
, insidious, and often fatal lung alloreaction that can
splantation (HSCT) or allogeneic lung transplanta-
roximately 2% to 3% of all allogeneic HSCTrecip-
-host disease (cGVHD) will develop this syndrome.
idence of BOS is higher. Unfortunately, the survival
mproved over the last 20 years. Attempts at clinical
tic criteria and inability to detect the syndrome at
tional Institutes of Health (NIH) consensus project
rding the diagnosis of BOS and monitoring of lung
nd poorly understood manifestation of cGVHD,
d is similar in pathology, clinical presentation,ndrome After AllogeneicBOS is a rare complication of allogeneic HSCT,
characterized by the new development of fixed airflow

Biol Blood Marrow Transplant 16:S106-S114, 2010 S107Bronchiolitis Obliterans Syndrome after Allogeneic HSCTobstruction after allogeneic HSCT. Depending upon
the definition used to define BOS, the prevalence of
this syndrome ranges from approximately 2% to 3%
among all allogeneic HCT recipients to 6% of patients
who develop cGVHD [1,4-6]. Studies that have used
more relaxed definitions have suggested that the prev-
alence may be even higher. We hypothesized that be-
cause this syndrome is characterized by airflow
obstruction, early rapid airflow decline, defined as an
annualized rate of 1-second forced expiratory volume
(FEV1) decline of 5% per year, might identify a popu-
lation at higher risk for poor outcomes [7]. This study
revealed that among all patients who receive an alloge-
neic transplant, 26% developed significant airflow de-
cline, and among patients who developed cGVHD,
30% had significant airflow decline after transplant.
Rapid airflow decline was also associated with signifi-
cant attributable mortality rates of 9% at 3 years,
12% at 5 years, and 18% at 10 years after transplant.
Mortality was much higher for the subpopulation of
patients with cGVHD (22% at 3 years, 27% at 5 years,
and 40% at 10 years) [7]. These results suggested that
the prevalence of airflow obstruction after allogeneic
HSCT may have been underestimated previously,
and the presence of rapid early airflow decline within
the first year after transplant is associated with signifi-
cantly increased risk for mortality even among long-
term survivors. As an effort to provide a uniformed def-
inition of BOS for clinical management and clinical
trials, the NIH recently provided new guidelines for
the diagnosis of nonpathologically confirmed BOS
(see later) [3]. Using this stringent definition, we con-
ducted an analysis that revealed an overall BOS preva-
lence of approximately 5.5%, with 10% in patients
surviving at least 1 year after transplant and 16% of
all patients with cGVHD (Jason Chien, personal com-
munication). Again, these data suggest that BOS is
likely under recognized in the transplant community.
Many risk factors have been found to be associated
with the development of BOS after allogeneic HSCT.
These include low IgG levels, the use of peripheral
blood stem cells (PBSCs), the use of busulfan (Bu) or
methotrexate (MTX) during the transplant process,
the intensity of the conditioning employed, and poor
pretransplant lung function and respiratory infection
during the first 100 days post transplantation [4,6-
10]. The clinical factor most commonly associated
with the development of BOS is the presence of
GVHD at another site [11-16]. In a study by Dudek
et al. [1], 81% of all of the BOS cases was diagnosed
with GVHD prior to the onset of BOS. Even in our
study assessing a milder definition of airflow obsruc-
tion, all of the patients who had significant early air-
flow decline had some form of GVHD at a site other
than the lung [7]. In the same study, older age at trans-
plant, poor lung function at baseline, and respiratory
viral infection within the first 100 days aftertransplant were also identified as risk factors for early
airflow decline. Additional analysis of the early respira-
tory viral infections revealed that most respiratory viral
infections during the first 100 days after HCT result in
fixed airflow obstruction at 1 year and lower respira-
tory tract parainfluenza virus infection was associated
with the highest risk for fixed airflow obstruction at
1 year (odds ratio, 17.9 [95% confidence interval
(CI), 2.0-160]; P 5 .01) [17].
Examination or pathologic samples have contrib-
uted to our understanding of BOS. Biopsy specimens
usually demonstrate bronchiolitis involving the small
airways and fibrinous obliteration of the lumen of the
respiratory bronchioles, with or without associated
interstitial pneumonia, fibrosis, or diffuse alveolar
damage; inflammatory cell infiltrates consisting of
neutrophils and mononuclear cells (MNCs), the for-
mer more often in the lumens of the affected bronchi-
oles, are prominent early in the disease process [18,19].
In the chronic phase, there are variable degrees of in-
tralumenal or peribronchiolar fibrosis, ranging from
proliferation of fibroblasts andmyofibroblasts to colla-
gen scarring. This leads to progressive circumferential
fibrosis and ultimate cicatrization of the small terminal
airways, manifesting as new fixed airflow obstruction.
Despite all the advances in stem cell transplantation
(SCT) over the last 2 decades, the cause of BOS is still
unknown. Allorecognition of lung antigens is the sus-
pected etiology of this disease because the 2 clinical sit-
uations associatedwithBOS involve alloimmunity, lung
transplantation—host (hematopoietic cells)-versus-
graft (lung) disease, and HCT—graft (hematopoietic
cells)-versus-host (lung) disease. Additionally, when
BOS occurs after HCT, it is typically accompanied by
alloimmune manifestations in other organs, for exam-
ple, liver, eyes, or skin. Indeed, the lung epithelium
may be the target of immune mediated-injury induced
by donor cytotoxic T cells in cGVHD [6], supporting
the hypothesis that BOS is a manifestation of cGVHD
in the lung. Unfortunately, there are no direct data to
support this statistical correlation; animal models of
graft-versus-host (GVH) reactions in the lungs primar-
ily result in alveolitis and interstitial infiltration with
lymphocytes and associated chemokines and cytokines
such as tumor necrosis factor (TNF) alpha. Unfortu-
nately, all of these studies have been conducted using
mouse models of host versus graft disease, which is
more representative of lung transplantation [18,20-24].
There is also substantial evidence from studies in
other airway diseases associatedwith chronic airway in-
flammation that endotoxin-induced cellular activation
and other components of the innate immune system
may play an important role in the pathogenesis, and
that the innate immune response is likely under genetic
control [25-28]. To test the hypothesis in the BOS set-
ting, we preformed a study using a gene-wide approach
to determine if genetic variation in the innate immune