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Bronchiolitis obliterans organizing pneumonia (BOOP)
was described in 1985
as a distinct entity, with different clinical,
radiographic, and prognostic features than the
airway disorder obliterative bronchiolitis
and the interstitial fibrotic lung disorder usual
interstitial pneumonia/idiopathic pulmonary fibrosis
(UIP/IPF).
BOOP is characterized by polyploid endobronchial
connective tissue masses composed of myxoid
fibroblastic tissue resembling granulation tissue
filling the lumens of terminal and respiratory
bronchioles and extending in a continuous fashion
into alveolar ducts and alveoli, representing an
organizing pneumonia.
Other histological features include central clusters
of mononuclear inflammatory cells possibly found in
the intraluminal polyps (the polyps appear to float
freely within a bronchiole or are focally attached
to the wall), chronic inflammation in the walls of
the surrounding alveoli with reactive type II cells,
increased foamy macrophages in the alveoli, and
preserved lung architecture.
BOOP continues to be reported throughout the world.
Most patients have idiopathic BOOP, but there are
several known causes of BOOP, and several systemic
disorders have BOOP as an associated primary
pulmonary lesion. The BOOP pattern might also occur as a
secondary process in several clinical settings, such
as the inflammatory-appearing lesion of UIP/IPF,
with Wegener granulomatosis, in the walls of lung
abscesses, around lymphoma or other neoplasms, and
with bronchiectasis. In these patients, the
underlying process is the primary cause of symptoms
and the subsequent clinical course.
The terms organizing pneumonia and cryptogenic
organizing pneumonia are sometimes used for the
broad category of patients with organizing
pneumonia. There are several reasons that the term
BOOP should continue to be used for the clinical
disorder and corresponding pathological lesion
described in this review. First, investigators and
clinicians throughout the world recognize the
clinical and pathological features of this disorder,
and they commonly use the term BOOP. Second, BOOP is
a histological process that involves distal airways
and alveoli simultaneously. Although various lung
diseases represent a chronic inflammatory process,
it is now apparent that the processes differ
markedly among various diseases, such as chronic
obstructive pulmonary disease, asthma, and BOOP,
with different inflammatory cells, mediators,
inflammatory effects, and response to treatment.
Therefore, an inflammatory lesion that involves only
airways or only alveoli may have different
inflammatory components than the BOOP lesion that
involves airway and alveoli simultaneously. Third,
investigations of specific treatments for BOOP will
be more strongly positive if the specific definition
of BOOP is used for inclusion of patients rather
than using the broad definition of organizing
pneumonia. This is similar to IPF, in which many
distinct histological disorders were included in
this category in the past, resulting in dilution of
the actual mechanism and poor treatment results. Now
that IPF is limited to UIP,3
the opportunity to fully characterize the fibrotic
pathway is much greater, and antifibrotic treatment
tailored to this fibrotic pathway will be tested
more efficiently and accurately.
Pathogenesis of BOOP
BOOP is an inflammatory lung disease and thus is
related to the inflammatory pathway rather than the
fibrosing pathway that occurs with UIP/IPF. The
inflammatory response associated with disorders such
as asthma, chronic obstructive pulmonary disease,
granulomatous diseases, and BOOP have common
features of the sequential inflammatory response,
yet these disorders seem to have differences that
have not yet been fully characterized. These
differences are important because treatment directed
toward one type of inflammatory response might not
be effective against another type.
There is newly formed fibromyxoid connective tissue
in BOOP and UIP/IPF; in BOOP it can be completely
reversed by corticosteroid therapy, but in UIP/IPF
this tissue participates in the remodeling and
destruction of the interstitium.
Reasons for the response to corticosteroid in BOOP
and the destruction in UIP/IPF remain unknown.
There seems to be abundant capillarization in the
intra-airway fibromyxoid lesions in BOOP compared
with minimal vascularization in UIP/IPF.
This might be because of vascular growth factors in
BOOP that will result in normal apoptosis
(natural-occurring cell death) in BOOP but not in
UIP/IPF. Results of an additional study
showed that the apoptotic activity is higher in the
fibromyxoid lesion of BOOP compared with UIP/IPF,
suggesting that apoptosis has an important role in
the resolution process of the newly formed
connective tissue in BOOP.
Diagnosing BOOP
Lung biopsy continues to be the preferred method for
establishing a diagnosis. The video-assisted
thoracoscopic procedure has become the established
technique. In a study
of 49 patients who underwent the video-assisted
thoracoscopic procedure for interstitial lung disease,
the mean length of the operation was 45 minutes, the
chest tube was inserted for 1.3 days, there were no
deaths, there were no reexplorations, and none were
converted to an open thoracotomy.
Radiographic findings of BOOP
The typical chest radiograph shows bilateral patchy
(alveolar) infiltrates. Cavities are rare, although 4 of 5 patients
with a single pulmonary nodule had cavitation.
Effusions are rare. Linear opacities occurring at the
bases are usually associated with a poorer prognosis;
however, a study
of BOOP in 23 patients in Korea indicated recovery in
all patients regardless of their radiographic findings.
Generally, the infiltrates gradually enlarge from their
original site or new infiltrates appear as the clinical
course progresses; however, migratory or "mobile"
pulmonary infiltrates have been reported in
10% to 25% of patients. Unilateral BOOP also has been
reported.
The chest computed tomographic scan shows findings
similar to the chest radiograph, with bilateral areas of
consolidation and ground glass opacities, usually with a
peripheral location. Costabel et al
reported that sometimes the peripheral opacities are in
the form of triangles, with the base of the triangle
along the pleural surface and the tip of the triangle
toward the mediastinum. In a study
from England, high-resolution chest computed tomographic
scans showed 2 types of linear opacities: the first
extends in a radial manner along the line of the bronchi
toward the pleura and the second occurs in a subpleural
location with no relation to the bronchi. Both types
usually occur in the lower lobes, frequently associated
with multifocal areas of consolidation, and usually
completely resolve with treatment.
Treatment of BOOP
Prednisone, with its potent anti-inflammatory property,
continues to be recommend as first-line treatment for
patients with symptomatic and progressive disease.
Patients with asymptomatic mass lesions or
nonprogressive disease can be observed and treated at a
later time if needed. The dosage is generally 1 mg/kg
(60 mg/d) for 1 to 3 months, then 40 mg/d for 3 months,
then 10 to 20 mg/d or every other day for a total of 1
year. Every-other-day scheduling can be successfully
used for this disorder. A shorter 6-month course may be
sufficient in certain situations. Total and permanent
recovery is seen in most patients and is somewhat
dependent on the cause or associated systemic disorders.
Anecdotally, erythromycin, inhaled triamcinolone, and
cyclophosphamide have been used to treat BOOP.
Epidemiological studies of these agents have not yet
been performed for confirmation of efficacy.
Recurrence of BOOP
In patients treated for less than 1 year, BOOP might
recur in one third. It is a lung disorder that can be
successfully treated a second and third time with the
previously responsive dosage level of prednisone.
Relapse of BOOP may be related to the severity of the
illness. In a group of 7 patients who had a relapse it
was found that the level of hypoxemia at the time of
diagnosis was the most important determinant of relapse;
however, Cordier
did not find this relation.
For patients who do not respond to treatment, it is
important to determine if the BOOP pattern is primary or
secondary. On close evaluation by a lung pathologist,
the biopsy specimen that shows the BOOP pattern might
also show the typical leading edge of "fibroblastic
foci" that indicates UIP/IPF. The BOOP pattern might
respond to corticosteroid therapy, yet the fibrotic
process of UIP/IPF is the driving force of the
progressively deteriorating clinical course.
Types of BOOP
Idiopathic BOOP is the most common type.
A flulike illness, fever, and an increased erythrocyte
sedimentation rate continue to be typical findings of
this form of BOOP. Cough and dyspnea are common but
generally mild. Hemoptysis is uncommon, although it has
been reported in 2 patients as a presenting symptom
and in some patients with nodules.
Crackles occur in two thirds of patients. Pneumothorax
has occurred as a complication of BOOP in one patient
with an effusion,
one with a solitary nodule,
and another with respiratory distress.
Results of pulmonary function studies show mildly to
moderately decreased vital capacity. The flow rates are
normal except in smokers. The diffusing capacity is
decreased in almost all patients, although generally
mildly to moderately. The prognosis of idiopathic BOOP
remains good, some patients resolve without treatment,
and 65% to 80% of patients treated with corticosteroid
therapy are cured.
Rapidly Progressive BOOP can occur in a small
percentage of patients, but it is a deadly form of the
disease. In
some of these patient reports, there was an underlying
fibrotic process as the cause of the ultimate fatal
course, with BOOP as a secondary component, yet some
patients seemed to have a primary, rapidly developing
BOOP, which had a better prognosis. This form of BOOP
occurs equally in men and women and at all ages. It can
occur in healthy, vigorous individuals or can be
associated with other systemic disorders. The course can
be rapid, with 1 to 3 days of symptoms and acute
respiratory failure. Patients might present with adult
respiratory distress syndrome, with pathological
findings indicating an organizing adult respiratory
distress syndrome pattern with the appearance of BOOP.
Clinically, rapidly progressive BOOP can be
indistinguishable from acute interstitial pneumonia.
Early histological diagnosis of the primary BOOP lesion
and initiation of corticosteroid therapy might improve
survival in these patients.
Focal Nodular BOOP was reported
in 1989 in 5 of 16 patients with idiopathic BOOP. Since
then it has become a clinically important process,
especially because it might be indistinguishable from
carcinoma of the lung.
Although some focal nodular lesions might progress to
the typical bilateral process of idiopathic BOOP, most
do not, and resection results in a cure.
Multiple Nodular Lesions can also occur, and
most regress spontaneously. Of 12 patients with multiple
large nodules or masses, all had complete resolution of
their symptoms, 10 with no therapy and 2 after
corticosteroid therapy.
In these patients, pleuritic chest pain was the most
common presenting symptom, occurring in 50%. The number
of masses varied from 2 to 8 (mean, 5). The authors
concluded that BOOP should be considered when multiple
large nodular lesions have chest computed tomographic
findings showing air bronchograms, irregular margins,
broad pleural tags, parenchymal bands, or subpleural
lines.
Clinician investigators
in New Orleans suggest that BOOP may have a connection
to reports of spontaneous regression of lung metastases.
They concluded that a major reason that reports of
spontaneous regression of lung metastasis have decreased
in recent years is the increasing emphasis on obtaining
diagnostic tissue of multiple nodular lesions for lung
metastasis, many of which have proven to be BOOP.
Postinfection BOOP can develop after a variety of
different types of infectious pneumonias,
including those caused by bacterial agents such as
Chlamydia,
Legionella, and Mycoplasma pneumoniae
and viral agents such as parainfluenza virus
and adenovirus.
Parasitic infections such as malaria
and fungal infections, including Cryptococcus
neoformans
and Pneumocystis carinii,
have also been reported as a cause of the BOOP lesion.
Generally for these patients, there is initial
improvement of the infectious pneumonia with use of
appropriate antimicrobial agents, but after a few days,
it becomes apparent that the symptoms and radiographic
findings persist. The pneumonia process has now become
organized into the BOOP lesion. Corticosteroid treatment
at this point is almost always successful.
Drug-related BOOP has been reported from
use of several different types of medications, including
anti-inflammatory and immunosuppressive agents such as
bleomycin sulfate, gold, and methotrexate; antibiotics
such as sulfasalazine, sulfamethoxypyridazine,
cephalosporins, and amphotericin B; illicit use of
cocaine; and a massive dose of L-tryptophan. Minocycline-associated
BOOP has been reported
in a woman who was taking this medication for acne.
Descriptions of amiodarone-related BOOP continue to be
reported.
Phenytoin-related BOOP with rapid improvement after
corticosteroid therapy has been reported.
There has been a report
of a woman who developed carbamazepine-induced lupus
erythematosus and associated BOOP, both of which
responded to corticosteroid therapy. There has been a
report
of ticlopidine hydrochloride, an inhibitor of platelet
aggregation, associated with BOOP that resolved after
withdrawal of the agent. BOOP has now been added to the
spectrum of pulmonary lesions associated with
nitrofurantoin.
Rheumatologic or connective tissue BOOP is
clinically similar to the idiopathic form and has been
reported
with all of the connective tissue diseases. BOOP
represents the patchy infiltrative lesions seen in
patients with lupus erythematosus, rheumatoid arthritis,
Sjögren syndrome, and dermatomyositis. The process often
responds to corticosteroid therapy, unlike the fibrotic
process that may occur in these disorders.
There has been a report of a patient with BOOP
associated with dermatomyositis that was resistant to
corticosteroid therapy; with initiation of
cyclophosphamide therapy, there was improvement of
pulmonary and cutaneous findings.
BOOP can also occur in patients with ankylosing
spondylitis,
polymyalgia rheumatica, and
Behçet disease
and might be the first manifestation of a connective
disorder.
Immunologic disease BOOP has been reported with
common variable immunodeficiency syndrome
and essential mixed cryoglobulinemia.
Bone marrow transplantation BOOP has been
described in patients who underwent allogeneic marrow
transplantation. There has also been a report of BOOP in
a patient who received a syngeneic bone marrow
transplant from his twin brother.
There is an additional report of a patient who developed
ulcerative colitis and BOOP 7 months after receiving a
bone marrow transplant from his brother.
It was not clear whether the BOOP was associated with
the ulcerative colitis or from another cause, such as a
cytomegalovirus infection. Too few reports have been
published to determine whether BOOP in these patients is
an incidental finding or represents a complication of
bone marrow transplantation.
Lung transplantation BOOP has been reported in
10% to 28% of lung transplant recipients. The lesion
generally occurs 1 to 10 months after transplantation
and is usually associated with the acute rejection
reaction. The process is reversible for most of these
patients, especially if the underlying acute rejection
is successfully treated. The BOOP lesion may occur
before the onset of obliterative bronchiolitis,
and whether this is a risk factor for lung
transplantation obliterative bronchiolitis has not been
established, but it is prudent to treat the BOOP
reactions aggressively in these patients.
Cytomegalovirus pneumonia-associated BOOP has also been
described
in lung transplant recipients and is generally
responsive to corticosteroid therapy.
Renal transplantation BOOP has been described
in 1 patient 12 weeks after transplantation. A rapid
recovery occurred after an increase of the daily dose of
methylprednisolone.
Radiotherapy BOOP has become an important
clinical disorder in patients receiving radiotherapy to
the breast.
Symptoms might occur 1 to 12 months after completion of
radiotherapy. Symptoms might be minimal, but most
patients have fever, nonproductive cough, and mild
shortness of breath. The chest radiograph shows
peripheral patchy or alveolar infiltrates, often outside
the radiation field.
One study
indicated that all 11 patients studied had
spontaneous migration of infiltrates from the irradiated
lung to the contralateral nonirradiated lung with no
nodular or reticular lesions. There can be a dramatic
improvement with corticosteroid therapy, but relapses
may occur. Some
investigators have
suggested that radiotherapy may "prime" the development
of BOOP. Bronchoalveolar lavage studies of these
patients indicate an increase in lymphocytes, mast
cells, CD3 cells, and CD8 cells and a decrease in CD4
cells and the CD4-CD8 ratio;
however, the underlying mechanism remains unknown.
Environment-related BOOP continues to be reported
rarely. In 1992, textile printing dye-related BOOP was
described in 22 textile airbrush workers.
Six died initially. Follow-up of some of the workers
indicated gradual improvement over time.
It has been suggested
that the cause was related to the spraying of a
respirable aerosol into the distal airways and alveoli;
however, the reactive chemical agent and mechanism
remain unclear. It is also not known whether the
organizing pneumonia was a de novo process or resulted
from the late organization of pulmonary edema.
Penicillium mold dust-related BOOP has been
described
in a patient who developed BOOP after inhalation of
powdery dust of a growth of Penicillium
janthinellum mold on the top of a discarded orange juice
container. Smoke inhalation BOOP has been reported
in a patient who was in a house fire and had erythema
nodosum.
Miscellaneous BOOP continues to be reported, eg,
in association with myelodysplastic syndrome,
Hunner interstitial cystitis,
chronic thyroiditis,
alcoholic cirrhosis,
and, in England, seasonal syndrome with cholestasis.
It has been reported in patients with human
immunodeficiency virus infection,
with one report during pregnancy.
Inflammatory bowel disease-related BOOP has been
described
as an important treatable disorder in these patients.
The BOOP lesion might be associated with lymphoma, and
an atypical course of what is thought to be idiopathic
BOOP may indicate a neoplastic process such as a
lymphoma.
Recurrent BOOP responsive to prednisone treatment has
been reported in T-cell leukemia. BOOP
has also been reported in primary biliary cirrhosis
and after coronary artery bypass graft surgery.
Conclusion
The busy clinician will see patients with a febrile
illness and patchy infiltrates who have not responded to
antibiotic drug therapy. The patient might have BOOP.
Sometimes this disorder is treated in the hospital, but
it is generally managed on an ambulatory basis. Typical
idiopathic BOOP is characterized by a flulike illness,
bilateral crackles, and patchy infiltrates and can be
cured in 65% to 80% of patients with prednisone therapy.
BOOP has become an important consideration in the
diagnosis of focal nodular lesions. Postinfectious
pneumonia BOOP remains a treatable process. BOOP occurs
in virtually all of the connective tissue disorders and
generally responds to corticosteroid therapy. It is an
important treatable inflammatory lung disease.
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Table 1. Classification of BOOP
Idiopathic BOOP
Rapidly progressive BOOP
Focal nodular BOOP
Post infection BOOP
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Chlamydia, Legionella
and Mycoplasma
Adenovirus, cytomegalovirus and influenza
virus
Malaria and Pneumocystis
Cryptococcus
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Drug-related BOOP
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Antibiotics:
Amphotericin B, cephalosporins,
minocycline, nitrofurantoin,
sulphasalazine,
and sulphamethoxypyridazine
Bleomycin and methotrexate
Gold
Amiodarone
Illicit use of cocaine
L-Tryptophan
Phenytoin
Cabamazepine
Ticlopidine
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Rheumatologic or
connective tissue disorders BOOP
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Lupus
erythematosus
Rheumatoid arthritis
Sjogren's syndrome and Sweet's syndrome
Polymyositis-dermatomyositis
Scleroderma - progressive systemic sclerosis
Ankylosing spondylitis
Polymylagia rheumatica
Behcet's syndrome
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Immunological
disorders BOOP
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Common variable
immunodeficiency syndrome
Essential mixed cryoglobulinemia
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Organ
transplantation BOOP
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Bone marrow,
lung and renal
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Radiation
therapy BOOP
Environmental exposures
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Textile
printing dye
Penicillium mold dust
House fire
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Miscellaneous
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Inflammatory
bowel disease
Lymphoma and cancer
T-cell chronic lymphocytic leukemia
Human immunodeficiency virus infection
Myelodysplastic syndrome
Hunner interstitial cystitis
Chronic thyroiditis
Alcoholic cirrhosis
Seasonal syndrome with cholestasis
Primary biliary cirrhosis
Coronary artery bypass graft (CABG) surgery
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Figure
1. A, Intraluminal
organization and polypoid granulation tissue within a
small bronchiole. B, Organization and polypoid
granulation tissue within small bronchioles, alveolar
ducts, and alveoli. The associated alveolar walls show
type II cell metaplasia and mild inflammatory
thickening. Courtesy of Thomas V. Colby, MD, Department
of Pathology, Mayo Clinic Scottsdale (Ariz) (both
parts). |
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Figure
2. A, Chest radiograph of a
54-year-old man with a flu-like illness, bilateral
crackles, decreased vital capacity, and a decreased
diffusing capacity that shows bilateral patchy
infiltrates in the lower lungs. B, High-resolution chest
computed tomographic scan shows areas of patchy
consolidation and ground glass opacities. Courtesy of
Philip Costello, MD, and Andetta R. Hunsaker, MD,
Department of Radiology, Brigham and Women's Hospital,
Boston, Mass. C, Chest computed tomographic scan shows a
triangular area of consolidation posteriorly.
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Gary R.
Epler, M.D.
Harvard
Medical School
Pulmonary and Critical Care Medicine
Brigham and Women's Hospital
Boston, Massachusetts
www.epler.com
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