Denise
R. Aberle,
MD
#{149} Gordon
Gamsu,
A combination of cytotoxic and corticosteroid therapy has dramatically improved the long-term survival of patients with Wegener granulomatosis. With extended survival, patients now experience diverse cardiopulmonary abnormalities that represent primary or secondary manifestations of the disease or that result from diagnosis and treatment. To evaluate these abnormalities, the authors reviewed the medical histories and chest radiologic findings of 19 patients with the histologic diagnosis of Wegener granulomatosis. In these patients thoracic images demonstrated parenchymal nodules or consolidations with cavitation, diffuse interstitial disease, mediastinal or hilar adenopathy, and isolated stenoses of the larynx or tracheobronchial tree. Intrathoracic relapse occurred in 18 cases; in onethird of these patients, findings at relapse differed from those at initial presentation. Complications from diagnosis or therapy occurred in nine patients. Pulmonary infection was the most frequent complication causing morbidity and was often clinically indistinguishable from the primary disease; it complicated relapse in five patients. The successful radiologic follow-up of patients with Wegener granulomatosis requires a consideration of the varied thoracic manifestations of both the primary disease and the complications of its treatment. Index Lung,
terms: Wegener diseases, 60.622
Radiology
1990;
From
Conte
the
accepted Current c RSNA,
Department
November address: 1990
gramulomatosis,
60.622
#{149}
174:703-709
Ave. Los Angeles,
fornia San Francisco meeting. Received 2
#{149} David
Lynch,
Thoracic Manifestations Granulomatosis: Diagnosis
,
I
MD
of Radiological
Sciences,
CA 90024 (D.R.A.),
W
MD2
of Wegener and Course’
granulomatosis is an idiopathic disease characterized by necrotizing vasculitis and gnanulomatosis. Although recognized as a EGENER
multisystem nant sites pamanasal
disorder, the predomiof involvement are the sinuses, lungs, and kidneys
(1). With the the prognosis matically remission tion (2).
use of cytotoxic of this disease
improved, is now As such,
agents, has dma-
and long-term a realistic expectain patients with
Wegener
granulomatosis, a variety of abnormalities are demonstrated that represent manifescardiopulmonary
tations plications
ment.
of the primary disease or comof its diagnosis or manage-
Early
recognition
abnormalities
of specific
is critical
ate intervention and bidity. To better characterize of thoracic
for
appmopri-
reduced
mom-
the
diversity in this
of California
San
Francis-
co with the histologic diagnosis of Wegener granulomatosis over a 19year period. We compared the dismanifestations with those
SUBJECTS
of this populareported in the litera-
AND
From 1969 to 1988, tologically confirmed matosis
were
seen.
All
cytotoxic
who
METHODS 19 patients Wegener patients
with hisgranulohad
cine
CT
University
Los Angeles,
University
School of Medicine, San Francisco (G.G., DL.). From the 1988 August 30, 1989; revision requested October 2; revision received 14. Address reprint requests to D.R.A. Department of Radiology, University of Colorado, Denver.
cyclophospha-
not
receive
therapy,
shortly
after
one
presen-
scans
(CT) scans (n
(n
1) of the
6), and
upper
airway.
dis-
1. Ten monary nodules
of Radiology,
did
ed tomographic
tions
of California
typically
tation. In the other patient, the diagnosis of Wegener granulomatosis was made only at autopsy. Sixteen patients were followed up at our institution; the duration of follow-up ranged from 1 1 months to 13 years. The mean duration of follow-up was 61 months ± 43 (mean ± standard deviation); the median duration of followup was 48 months. Images demonstrating pulmonary abnormalities at presentation and during follow-up were reviewed for each patient and consisted of chest radiographs (n 19), conventional lung tomograms (n 2), tracheograms (n 1), thoracic comput-
ease involving the paranasal sinuses, the lungs (including isolated or concomitant airway disease), or the kidneys. In 16 patients, two or more of these sites were involved. Intrathoracic involvement with Wegener granulomatosis was present in 18 patients at initial presentation or at
and the Department
agents,
mide. High-dose corticosteroids were given concomitantly, and the dose was tapered to the lowest effective dose. Administration of cytotoxic agents was continued from several months to 1 year after response or remission. Of the two subjects
population, we reviewed the medical records of all patients seen at the
ease tion tune.
point during the course of the disOne subject initially had only cutaneous and renal disease; lesions of the hypopharynx occurred at relapse. In all patients, the diagnosis of Wegener granulomatosis was established from histologic examination of tissues obtained from the lungs or conducting airways (n 11), the nose or paranasal sinuses (n 9), the kidneys (n = 6), the skin (n 4), or the heart (n 1). In 12 patients, representative histologic specimens were present from two sites. Seventeen patients were treated with ease.
was lost to follow-up
manifestations
University
some
10833
Le-
of Cahi-
RSNA annual November 10;
RESULTS Initial The
Pulmonary initial of the
Manifestations
pulmonary disease
are
manifestalisted
in Table
of 19 patients had classic findings of parenchymal (Fig la); in all but one
tient, the nodules were multiple. Nodules were of varying sizesranging from several millimeters
several lateral,
centimeters-were and had no regional
pulpa-
to
usually bidistnibu703
Figure 1. Preliminary chest radiographic findings in three patients with Wegener granulomatosis. (a) Typical presentation of parenchymal nodules, some with cavitation (arrows). Paratracheal and right hilar adenopathy is also present. Adenopathy occurred in three of our patients; however, in none was it an isolated intrathoracic finding. (b) Cavitary air-space consolidation, initially misdiagnosed as infectious pneumonia. (c) Collimated view of the right lower lobe demonstrates prominent reticular and bronchovascular markings bilaterally without focal
masses.
gener
Transbronchial
biopsy
findings
demonstrated
small
vessel
vasculitis
and
sterile
necrotizing
granulomas
characteristic
of We-
granulomatosis.
tion. In seven patients, the nodules were cavitary. Cavitary air-space consolidation (Fig ib) initially thought to represent necrotizing bacterial pneumonia
was
seen
in
two
Table
1
Initial
Parenchymal
the bronchovascuinterstitium was prominent without discrete puimonary nodules (Fig ic). Both patients had multisystem disease involving the paranasal sinuses, kidneys, or
sites.
Results
from
Granulomatosis
in 19 Patients No.
of Patients
findings
14
Nodules
3 7
Cavitary nodules Focal air-space disease
simulating
Increased bronchovascular Airway lesions
Larynx Trachea Main-stem Other
transbron-
chial biopsy in both patients strated necrotizing vasculitis tent with findings in Wegener
of Wegener
Feature
patients.
In two patients lar and peripheral
other
Manifestations
Thoracic
cavitary
pneumonia
2
lines
2 2
2 2 1
(intrathoracic) bronchus
Adenopathy
demonconsisgran-
Mediastinal Hilar Normal chest
3 2 3 3
radiographs
ulomatosis.
Adenopathy tinum
of the
was
In each
present
case
findings
three
adenopathy
conjunction
with ties
hila
in
with and
or mediaspatients.
occurred
other
regressed
the accompanying during the course
intrathoracic
in
changes ration
in
appropriate
concert
abnormaliof cytotoxic
low
Two patients presented with stnidor and/or hoarseness in the absence of pulmonary parenchymal disease. In both endoscopy revealed circumferentiai narrowing of the glottis and infraglottic airway. In one patient, a vocal cord granuloma was found to be the cause of hoarseness, and tracheostomy was performed to bypass the laryngeal obstruction. In the other patient, CT was performed to depict the airway distal to the narrowed larynx (Fig 2). Conventional CT mevealed severe soft-tissue thickening of the larynx and diffuse circumferential narrowing of the trachea and proximal
main-stem
Cine cheal 704
was
bronchi.
irregularly
CT was performed compliance and
Radiology
#{149}
Trache-
calcified. to assess dynamic
tra-
in the was
airways during used to determine
site
the
level
ryngeal
therapy.
al cartilage
and
for
respithe bela-
tracheostomy
of the
most
severe
stenosis.
In three patients, results from the initial chest radiographs were normal. One patient has never developed intrathoracic manifestations of
disease;
the
histologic
diagnosis
Wegener granulomatosis on representative renal
opsy
findings.
tients
with
presentation, way
lesions
In the normal
other
two
radiographs
upper
and
developed
of
was based and nasal bi-
lower
at the
paat air-
time
of
relapse.
lapse
or
despite apy, nosis
or
lung
Pulmonary
Complications
of Disease
Course
tions
of
initial
to diag-
Wegener
2).
six
patients
airway
were
different
pulmonary (eg,
in
one
relapse
each
cavitary
these
was
manifested
without
were
case
the
nodules, was
stenosis
pulmonary
in
patient
manifestation
parenchymal
nodules
from
involvement
pulmonary
whereas
me-
of
(Table
relapse
the
disease). Recurrent
representing
disease
and (c) pulmonary as consequences of disorgan systems without
vasculitis
The pulmonary abnormalities that occurred in the course of disease were of three major types: (a) cardio-
disease
initial
Manifestations of relapse-There were 26 episodes of relapse necessitating hospitalization of the patient or significant alteration of chemotherapy. Of these, 18 relapses involving the lung or airways occurred in 13 patients. Pulmonary manifesta-
cavitary
during
of
pharmacotherrelated
management
granulomatosis, abnormalities ease in other
initial
the
progression
appropriate (b) complications
seen
had
as
parenchymal parenchymal
in
six
been
cases;
the
in
initial
March
1990
were
thought
vaivular
The
to be consistent
Wegenem
patient
was
phosphamide
had
with
granulomatosis.
treated
and
successful
with
cyclo-
conticosteroids
remission
and
of hem pul-
monary
lesions
without
of other
cardiac
abnormalities.
development
Diffuse pulmonary hemorrhage developed in two patients with cavitary pulmonary nodules at initial presentation findings
2.
Images of a 26-year-old man with diffuse wheezing and stridor. At direct laryngoscopy there was severe thickening of the aryepiglottic folds and circumferential narrowing of the larynx; the lower airways could not be depicted, and CT was performed to assess the patency of the tracheobronchial tree. (a) CT scan with soft-tissue window at the level of distal trachea shows circumferential narrowing and soft-tissue thickening with scattered foci of calcification (arrowhead). (b) CT scan with lung window at the level of the main-stem bronchi demonstrates similar soft-tissue thickening (arrows) and narrowing. These changes were continuous with the level of the bronchus intermedius.
Table 2 Thoracic
Complications
during
the Course
of Disease
Feature
No.ofCases __________
18
Cardiopulmonary relapse* Parenchymal nodules Multifocal parenchymal infiltrates Diffuse pulmonary hemorrhage Aortic valvulitis Airway disease Hypopharynx
or other
Pulmonary
7
Superinfection
in preexisting cavities pneumonia Acute alveolar damage (cyclophosphamide-induced) Systemic air embolism after fine-needle aspiration of a vasculitic Extrathoracic relapse Hydrostatic edema secondary to renal failure Diaphragmatic paralysis secondary to phrenic neuropathy *
There
were
18 relapses
among
2 lesion
3 2 1
relapse was insufficiency and progressive tions of the earlier, the resection of per lobe; at was interpreted with sterile
manifested as acute aortic with pulmonary edema cavitary consolidaupper lobes. One year patient had undergone a nodule in the right uphistologic examination it as subacute abscess granulomata. At second
recurrent
admission,
emergency
replacement
was
matosis.
Wegener
granulo-
recurred
sinusitis,
taneous
episclenitis,
or
cu-
vasculitis.
In two chymal
lapse. lobe
of Nodules
patients,
multifocal
consolidations
heralded
In the first, consolidations
withdrawal
of
right and occurred
parenme-
left lower after
cyclophosphamide.
Cavitary pulmonary consolidation had been the initial pulmonary manifestation of Wegener granulomatosis in this patient. In the second patient,
Volume
174
Number
#{149}
3
with
presence rophages
sumed
bacterial
logic
examination
of the
bacterial vegetations. the original lung classic
and
small
identified.
aortic
that
vessel The
valve without
On histologic
features
granulomatosis,
pre-
Histo-
inflammation
review speci-
site
and
of hemosidenin-laden compatible with
bleedthe mac-
diffuse
of treatment presentation.
and
died
2 weeks
lesions occurred in the course of eight
in five parelapses.
debilitating
sites
gallium
activity
tric
granulomata
medius
lapse, tions
focal
at scattered
corresponding seen
at
to the
narrowing
abnormal
of cytotoxic persistent of
right
in all pa-
the
drugs. concen-
bronchus
middle repeated bronchoscopic of granulation tissue and
in-
airway
CT. Therapy
tients consisted one patient with
Wegener
radionuclide
demonstrated
creased
is,
were findings
hoarseness,
patient,
scanning
areas
of
by
cough, stnidor, or reduced exercise tolerance. Chest abnormalities were evident in three patients and consisted of focal or diffuse narrowing of the trachea and main-stem bronchi. In one patient, bronchial narrowing had resulted in right middle lobe collapse. In two patients whose proximal airway disease prevented bronchoscopic evaluation, CT revealed mucosal thickening with on without calcifications at sites of involvement.
of
vasculitis, aortic valve
diffuse
localized
pulmonary hemorrhage. In both patients, acute glomerulopathy occurred concomitantly or within 2 weeks of pulmonary hemorrhage. One patient responded to high-dose corticosteroid and cytotoxic therapy; the second succumbed to complica-
In one
valve
for
endocarditis.
demonstrated
men,
aortic
performed
diffusingIn each patient
revealed no
heralded
13 patients.
while cytotoxic therapy was being tapered or after variable periods of complete disease remission without drug themapy. In each case, symptoms of accelerated disease were found in locations other than the lower respiratory tract and included epistaxis,
manifestation
patients in-
In two patients, airway occlusion had been the initial manifestation of Wegener granulomatosis; in the others, there was either no pulmonary disease at diagnosis (n 2) or initial disease was confined to the pulmonary parenchyma (n 1). The distribution of airway disease was variable and extended from the hypophanynx to the segmental bronchi. In each case, recurrence was symptomatic and was
Leucopenia-related Unrelated
ing
Airway
9
complications
infection
bronchoscopy
tients
4
Main-stem bronchi Lobar collapse
one patient, single-breath capacity was elevated.
tions after
2 1
Larynx/trachea Treatment-related
3). In both presentation
cluded acute dyspnea, anemia, and hypoxemia without hemoptysis. Chest radiographs revealed diffuse bilateral air-space consolidation. In
b. Figure
(Fig at second
In
inter-
lobe
colresec-
were
Radiology
705
#{149}
unsuccessful in relieving the obstruction, and local radiation therapy was given with limited success. Other pulmonary complications. -In 12 instances, pulmonary complica-
I
I
w-
tions occurred in the course of diagnosis or treatment of Wegener granulomatosis (Table 2). Seven of these
were cases, years
related to infection. pneumonia occurred after initial granulomatosis; pneumonia of initial
gener tients, months
In five several
.;
diagnosis
of Wein two paoccurred within 3 diagnosis and prior
to successful remission. Five of the cases of pneumonia were associated with
..1
relapse.
Two
cases
of pneumonia
were
tem-
3.
4.
poraily related to severe neutropenia due to cyclophosphamide administration. Relapse findings in one patient included rapidly progressive glomerulonephnitis and central nervous system vasculitis with grand mal seizures. Cyclophosphamide had
Figure
been discontinued 1 week earlier because of declining peripheral leucocyte counts. Spiking fevers developed in the patient with diffuse air-
anterior chest consolidation nas aeruginosa. nary infection.
space
and
at the Open
time lung
cystis
interstitial
which
resolved
with
pentamidine therapy and restoration of neutrophil counts. A second patient was given cyclophosphamide for active vasculitis with diffuse pulmonany hemorrhage and renal insufficiency. Severe neutropenia developed, and the patient died of overwhelming Staphylococcus aureus
findings of spiking fevers pharmacologic control of
vasculitis, new acute changes graphs including solidation (Fig
levels
productive cough, seen on chest radioprogressive con4) or new air-fluid
in preexisting
cavities.
Two
or
of
these patients had concurrent paranasal sinus involvement; the pulmonary pathogens were the same as those cultured from the paranasal sinuses, suggesting that the pneumonia represented contamination from the upper airways. In the third patient, pneumonia was temporally melated to fibemoptic bronchoscopy.
In two
instances,
bacterial
pneu-
monia occurred in the absence of active pulmonary involvement by Wegenem granulomatosis. In one, right lower lobe pneumonia developed distal to a focal airway stenosis
706
Radiology
#{149}
of a 59-year-old
woman
with
a 4-year
history
of Wegener
gran-
ulomatosis with sinusitis, episcleritis, cutaneous vasculitis, and cavitary pulmonary infiltrates. At presentation the patient had marked dyspnea, hypoxemia, anemia, and chest radiographic evidence of bilateral consolidations of the middle and lower lobes. The patient died, and at autopsy the lung histologic findings were compatible with diffuse pulmonary capillaritis. (4) Radiograph of a 60-year-old man with sinusitis and chronic cavitary lung nodules secondary to Wegener granulomatosis. The patient had long-standing bacterial colonization
of the paranasal
sinuses. radiograph of the right The patient
He presented
with
demonstrates upper lobe. was treated
increasing
dyspnea
multiple bilateral Sputum and sinus successfully with
caused by Wegener granulomatosis. Poor local clearance mechanisms were thought to contribute to the development of this complication. One patient with recurrent episclenitis and cavitary parenchymal nodules experienced progressive dyspnea while receiving maintenance therapy with cyclophosphamide. Chest radiographs appeared un-
changed,
pneumonia with septicemia. Secondary infection of cavitary nodules occurred in three patients with active Wegener granulomatosis. Supeninfection was suspected from
the clinical after initial
(3) Radiograph
and
cavitary cultures antibiotics
spiking
fevers.
nodules and were positive for intercurrent
Postero-
new cavitary for Pseudomopulmo-
consolidations
of severe neutropenia. biopsy revealed Pneumo-
carinii,
3, 4.
but
high-resolution
CT
scans demonstrated patchy groundglass opacification not evident on plain radiographs (Fig 5). Transbronchial biopsy was performed to exdude intercurrent infection and revealed diffuse alveolar damage typical of cyclophosphamide-induced lung injury. In one patient reported previously (3), a fatal systemic arterial air embolism occurred during percutaneous fine-needle aspiration of a lung lesion.
Air
emboli
were
believed
to
have been introduced by coughing after puncture of diseased pulmonary venules. Three patients developed pulmonary complications related to vasculitis in extrathoracic sites. In two, symptoms of acute dyspnea and hemoptysis developed in temporal relation to progressive renal failure. In both patients, hydrostatic pulmonary edema resolved after hemodialysis and restoration of the normal intravascular volume. In another patient,
diaphragmatic in
the
dysfunction
setting
of
left
neuropathy.
Chronic
lyneuropathy
was
Wegener
occurred
phrenic
nerve
peripheral
po-
a manifestation
granulomatosis
of
in this
pa-
tient.
DISCUSSION Wegener granulomatosis is a disease of unknown cause that was first defined in 1936 (1). It is generally considered a hypersensitivity disorder with granulomatous inflammation,
small
vessel
lonephritis,
vasculitis,
and
vation
the
of circulating
immune
glomeru-
occasional
and
complexes.
A
obser-
deposited limited
form
without renal involvement has also been described (1,2). Prior to effective pharmacotherapy, death typically
resulted
from
renal
failure
after
an
average of 5 months, and fewer than 10% of patients survived 2 years after diagnosis (2). The routine administration of cytotoxic agents, particularly cyclophosphamide, conjunction
effected
long-term
majority
of
continued
complete ing
the
tative
generally
histologic
has
remission at
in the
Therapy least
remission, exposure
or in
corticosteroids,
patients. for
toxic side effects The diagnosis matosis
alone
with
thus of
is often
1 year
after
lengthen-
patients
to
the
of these agents. of Wegener granulorequires
findings
represen-
from
March
one
or
1990
b. Figure 5. Images of a 56-year-old for over 7 years. At presentation phamide-induced py there was
nodules plained from
acute paradoxic
(arrows) dyspnea the
lower
alveolar motion
correspond and showed lobes
woman with multisystem she had increasing exertional damage. of the left
to sites patchy
revealed
diffuse
(a) Frontal hemidiaphragm,
of involvement ground-glass alveolar
more sites of involvement. Pathologic changes from lung biopsy specimens are the most conclusive, since findings from other sites such as the upper respiratory tract or kidneys may be nonspecific. Recently, the presence of anticytoplasmic autoantibodies in the serum has been found to be highly specific for the diagnosis
of Wegener rum titers
granulomatosis,
and
se-
vary in response to disease activity (4). However, at present, the finding of anticytoplasmic autoantibodies is not uniformly considered an alternative to a histologic diagnosis. Generally, the pathologic diagnosis requires biopsy, typically by means of open thoracotomy. Percutaneous cytologic sampling under radiologic guidance does not provide sufficient material to demonstrate the histologic changes and may be complicated by uncontrolled hemoptysis, coughing, as occurred However, termining
or systemic air embolism in one of our patients. CT may play a role in dethe optimum site for biopsy by defining those sites in which necrosis has not occurred. The lower respiratory tract manifestations of Wegener granulomatosis are protean. Pulmonary parenchymal features were the first to be descnibed (5-9). Of these, cavitary nodules that may be transient and recurrent (5,8) are the classic and most common pattern of intrathoracic disease. Segmental or lobar consolida-
Volume
174
Number
#{149}
3
chest
involvement dyspnea
radiograph presumed
by Wegener opacification
damage
by Wegener was found
demonstrates to represent
granulomatosis controlled with to have left phrenic neuropathy
new phrenic
elevation neuropathy
with
CT was performed lobes. Transbronchial
cyclophosphamide-induced
radiographically from pneumonia described (8,10).
lung
been
nodular
tients
with
or reticulonodular interstitial temns may occur (9). In most parenchymal involvement,
patcases of histologic
(16).
One-half
tients
have
voice
change,
examination
lung
some,
upper
of our
patients,
of the
diffuse
affected
me-
veals necrotizing granulomata with vasculitis. Diffuse pulmonary hemorrhage is a serious, typically fulminant manifestation of lower respiratory involvement (11-13). Pathologic examination of the lung reveals extensive vasculitis of small arteries, veins, and capillaries; granulomatous changes may be inconspicuous or absent, and there is no consistent immunofluorescent pattern of immune
complex
deposition
(14,15).
In many
of the reported cases of pulmonary hemorrhage with Wegenem gmanuiomatosis, concurrent renal failure has been present, which may result in the erroneous diagnosis of Goodpasture disease despite the absence of demonstrable antiglomerular basement membrane antibody. The airway manifestations of Wegener granulomatosis have received increasing attention over time. This probably reflects both a heightened awareness of the disease as well as an increased frequency due to extended survival of treated patients. The frequency of airway disease is difficult to estimate because most derived from retrospective
reports case
are stud-
At fluoroscoparenchymal
to evaluate unexbiopsy specimens
disease.
indishave As with
two
are
cyclophosphamide as well as cyclophos-
of the left hemidiaphragm. from vasculitis. Small
granulomatosis. (b) High-resolution bilaterally in the middle and lower
compatible
tions that tinguishable also been
and
ies with poor tion. Laryngeal
pathologic involvement
described
documentahas
in up to 25% of paWegener
granulomatosis
or more
of affected
symptoms
pa-
of hoarseness,
or dyspnea airway
(16,17).
stenosis
tates tmacheostomy, two patients in our
In
necessi-
as occurred in series. Lesions
usually affect the subglottic larynx, less often affect the true vocal cords
or epiglottis,
and
may
be ulcerative
or proliferative (16). Histologic mens may show only granulomas without vasculitis (18); in these the diagnosis can be established
disease such neys,
in other as the lung or paranasal
specicases, from
characteristic
areas,
pamenchyma, sinuses.
kid-
Subacute or chronic tmacheobronchial involvement (10,19-22) may
me-
suit in lobar collapse or obstructive symptoms. Disease may be unifocal or multifocal and may involve short or long segments of the intrathomacic trachea and main-stem bronchi. CT can be used to define precisely the site (or sites) of airway involvement, the severity of narrowing, and both intraand extraluminal soft-tissue components. In some of our patients,
severe
upper
airway
stenosis
pre-
cluded bronchoscopic evaluation of the lower respiratory tract, and CT was pivotal in characterizing widespread narrowing of the tmacheobronchial tree. CT can also serve as
Radiology
707
#{149}
the preoperative map for proposed tnacheostomy or bronchoplastic procedures and may obviate more invasive imaging studies such as tmacheobronchography. Cine CT, performed in one of our patients, extends the usefulness of CT by demonstrating dynamic airway changes in response to respiratory maneuvers (21). Cyclophosphamide therapy has a variable effect on airway disease. In our experience, parenchymal lesions in Wegenem gmanulomatosis were more responsive to treatment than were airway obstructions. Some patients experience symptomatic improvement without an appreciable change in cross-sectional measures of obstruction or abnormalities on flow volume loops. In others bronchoplasty, sleeve resection of involved bronchi, or local radiation therapy have been attempted (19). The frequency of relapse and the propensity of this disease to recur in different sites has been proposed as a reason for the limited success of surgical mepair (17). In addition, some reports indicate that the persistent obstruction may be biologically inactive, consisting of granulation tissue and fibrosis (18). A variety of less common intrathomacic manifestations in Wegener granulomatosis have been reported. Pleural thickening, effusions (7,10), and, rarely, hydropneumothorax (10,23) have been described. Mediastinal or hilar adenopathy occurs infrequently (8,24), typically with other pulmonary manifestations of disease, and is thought to represent reactive hyperplasia in the setting of an active inflammatory process. To our knowledge, phrenic nerve neuropathy resulting in diaphragm dysfunction has not previously been meported, although peripheral monoand polyneuropathy are well known consequences of Wegener granulomatosis (5). There have been several reports of cardiac lesions in patients with Wegener granulomatosis (1,5,19). Necrotizing coronary vasculitis and pancarditis are most frequent; isolated valvular lesions, granulomatous inflammation of the epicandium, focal myocardial necrosis, penicarditis, and endocardial mural thrombi have also been described. Patients may develop refractory arrhythmias, congestive cardiomyopathy, or acute pulmonary edema, as occurred in one of our patients. The morbidity in patients with cardiac involvement is high. Finally, pulmonary edema may complicate cases with renal involvement in 708
Radiology
#{149}
the absence of active cardiopulmonary disease. Any of the pulmonary manifestations of Wegenem granulomatosis may occur at initial presentation or at relapse. As well, the pattern of disease expression in the individual patient may vary from one episode to another. In our experience, symptoms were most conspicuous in patients with airway disease or diffuse pulmonary hemorrhage and included fever, hemoptysis, dyspnea, or stnidor. In patients with cavitary masses or nodules, the onset of active disease was typically heralded by symptoms in locations other than the lung, such as the upper respiratory tract or nervous system. In many instances, relapse occurred in the setting of tapering cytotoxic therapy as has been previously reported (2). Given the protean manifestations and chronicity of Wegener granulomatosis,
primary
difficult cations tion.
disease
may
be
to distinguish from compliof therapy or secondary infecIn patients
with
upper
respira-
tory tract symptoms, secondary infection of the paranasal sinuses is more common than relapse of the primary disease (2). Interestingly, in two of our patients with bacterial pneumonia, the same organisms were responsible for chronic, smoldering pamanasal sinus infections. These patients may have developed intercurrent pneumonias by means of contamination from the upper respiratory tract. The frequency of pulmonary infection
in our
patients
was
comparable
to that described by others (25). Patients with pneumonia frequently have fever, pulmonary symptoms, and elevations of erythrocyte sedimentation rate comparable to findings at relapse. Furthermore, in the lower respiratory
tract
relapse may be
complicated by intercurrent pulmonary infection (25) and occurred in five of our patients. Radiographic changes such as increasing consolidation or the development of aim-fluid levels within cavities are not specific but may reflect intercurrent infection. An association between relapse and infection has been described in a prospective, longitudinal study of patients with Wegenem granulomatosis
by
Pinching
et al (25).
Among
18
patients, nine of 20 relapses were associated with intercurrent infections. Funthenmore, the site of infection appeared to determine the site of melapse; of six respiratory infections, all were associated with pulmonary relapse. In their study (25), successful
treatment generally required treatment of the infection as well as escalation of immunosuppressive therapy. The authors contended that infection may precipitate relapse through
reactivation of infection-derived cmculating immune complexes, or that the acute-phase or cellular response to infection may enhance quiescent disease. Given the apparent association
between
relapse
and
infection
and the similarity of their symptoms, chest radiographic evaluation for infection is indicated for any increase in systemic or pulmonary symptoms and during the tapering of cytotoxic drugs or corticostemoids in patients with known lower respiratory tract
involvement. Cytotoxic
treatment
granulomatosis
has
once
almost
into one remission
of Wegenem transformed
uniformly
a
fatal
disease
with potential for long-term or cure. Active vasculitis
of
the central nervous system, kidneys, and lungs may be fulminant, and the delay of appropriate cytotoxic therapy in these cases has been implicated as a major cause of morbidity (2,5). However, the potential side effects of cytotoxic agents place patients at risk for a variety of complications. Semious infection resulting from cyclophosphamide-induced immune suppmession occurred in two of our pa-
tients.
In addition,
undiagnosed istration
sumed
in patients
relapse
Drug-related interstitial
could
be catastrophic.
alveolar fibrosis are
damage known
ae of cyclophosphamide tion
with
pneumonia, the adminof cytotoxic agents for pre-
(26)
but
and sequel-
administra-
may
be
difficult
to ap-
preciate on chest radiographs in the presence of pulmonary pamenchymal vasculitis. In one of our patients with progressive dyspnea and stable chest radiographs, high-resolution CT was performed to better evaluate parenchyma. Unsuspected ings prompted biopsy and tion of drug-induced lung
the lung CT findconfirmainjury.
The intrathomacic manifestations of Wegenem granulomatosis are multipie and varied. Parenchymal involvement is the most typical expression
of disease;
rience
however,
isolated
stenoses
are
in our
or concomitant common.
expe-
airway
Cardiac
in-
volvement has also been reported to occur in up to 30% of patients. In the individual
relapse tial
vival,
patient,
often
manifestations
differ
presentation.
a variety
plications may as the consequence
involvement;
from With
of
those
at
extended
sum-
of intrathoracic result
these
corn-
from therapy of extrathoracic
may
mi-
have
or
pro-
March
1990
found impact on the course of the disease on may be confused with pnimary lower respiratory tract involvement. Pulmonary infection is the most frequent and potentially serious complication, since the failure to necognize infections can have serious consequences in patients receiving immunosuppressive therapy. Thomacic imaging plays a key role in the evaluation and monitoring of patients with Wegenem granulomatosis.
Successful
madiologic
plasmic
Wolff SM, Fauci AS, Horn RG, Dale DC. Wegener’s granulomatosis. Ann Intern Med 1974; 81:513-525. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with for
21 years.
Ann
Intern
5.
6.
Number
#{149}
3
in
their
16.
17.
immuno-
Wegener
granuloma-
Ann Intern Med 1989; 111:28-40. AS, Wolff SM. Wegener’s granulo-
tosis. Fauci
studies
in eighteen
patients
review of the literature. 52:535-561. McGregor MBB, SandIer
and
Medicine G.
18. a
1973;
19.
Wegener’s
granulomatosis: 7.
a clinical and radiologic J Radiol 1964; 37:430-439.
Br
Gonzalez er’s
L, Van
9.
HS.
review
1973;
of
Wegen-
tosis.
AJR
Maguire
20.
1 1 cases.
107:295-300.
Gohel VK, Dalinka MK, Israel HL, Libshitz HI. The radiological manifestations of Wegener’s granulomatosis. Br J Radiol 1973; 46:427-432. Landman 5, Burgener F. Pulmonary
manifestations 10.
Ordstrand
granulomatosis:
Radiology
8.
in Wegener’s 1974;
21.
granuloma-
122:750-757.
R, Fauci AS, Doppman
SM. Unusual radiographic Wegener’s granulomatosis.
JL, Wolff
22.
features of AJR 1978;
130:233-238. 1 1.
12.
Hensley MJ, Feldman NT, Lazarus Galvanek EG. Diffuse pulmonary rhage and rapidly progressive renal ure: an uncommon presentation of gener’s granulomatosis. Am J Med 66:894-898.
Albelda
SM, Gefter
DM,
pulmonary classification.
Stokes
BG, Rees RT, Sims EH,
TC, McCann
Grupe WE, Colvin year-old boy wtih
Thorax
1982;
CA.
Wegener’s
granulomatosis:
a
radiological review of the pulmonary manifestations at initial presentation and during relapse. Clin Radiol 1982; 33:545551. Stein MG, Gamsu G, Webb WR, Stulbarg MS. Computed tomography of diffuse tracheal stenosis in Wegener granulomatosis. J Comput Assist Tomogr 1986; 10:868-870. Cohen MI, Gore RM, August CZ, Ossoff RH. Tracheal and bronchial stenosis associated with mediastinal adenopathy in Wegener granulomatosis: CT findings. J Comput Assist Tomogr 1984; 8:327-329. Epstein DM, Cefter WB, Miller WT, Cohel V, Bonavita JA. Spontaneous pneumoan
uncommon
manifestation
granulomatosis.
Radiology
of
1980;
135:327-328. 24.
Nichols L. A 31-year-old woman with cough, hemoptysis, and bilateral hilar adenopathy. JAMA 1983; 249:2691-2692. Pinching AJ, Rees AJ, Pussell BA, Lockwood CM, Mitchison RS, Peters DK. Re-
lapses
37:315-316.
EJ. A 15and occult
Farelly
thorax:
fulminating intrain Wegener’s
RB, Mark hemoptysis
Thomas K. Laryngeal manifestations of Wegener’s granuloma. J Laryngol Otol 1970; 84:101-106. McDonald TJ, Neel HB, DeRemee BA. Wegener’s granulomatosis of the subglottis and the upper portion of the trachea. Ann Otol Rhinol Laryngol 1982; 91:588592. Talerman A, Wright D. Laryngeal obstruction due to Wegener’s granulomatosis. Arch Otolaryngol 1972; 96:376-379. Flye MW, Mundinger GH, Fauci AS. Diagnostic and therapeutic aspects of the surgical approach to Wegener’s granulomatosis. J Thorac Cardiovasc Surg 1979; 77:331-337.
Wegener
hemorR.adiol-
blood in the urine. Massachusetts General Hospital Case Records, case 12-1986. N
Med
23.
25.
BDW. Acute haemorrhage
granulomatosis.
14.
WB, Epstein
JM, hemorfailWe1979;
Miller WT. Diffuse rhage: a review and ogy 1985; 154:289-297. Harrison pulmonary
15.
174
value
matosis:
1983; 98:76-85.
Volume
autoantibodies:
diagnostic
13.
85 patients
Aberle DR, Gamsu G, Goldon JA. Fatal systemic arterial air embolism following lung needle aspiration. Radiology 1987; 165:351-353. N#{246}lleB, Specks U, L#{252}demann J, Rohrbach MS. DeRemee RA, Gross WL. Anticyto-
survey.
References
2.
4.
evaluation
requires familiarity with the myriad intmathomacic manifestations of the disease, knowledge of the potential for other associated complications, and careful correlation of findings with patient symptoms and treatment. CT can accurately help confirm the presence and extent of airway involvement, particularly in patients for whom upper respiratory tract obstruction precludes direct endoscopy, and is an important adjunct in the surgical planning of bronchoplastic or other corrective procedures. Finally, imaging guidance may be useful to determine appropriate sites for biopsy to provide histologic or microbiologic analysis. U
1.
3.
26.
in Wegener’s
granulomatosis:
the
role of infection. Br Med J 1980; 281:836838. CooperJAD, White DA, Matthay BA. Drug-induced pulmonary disease. I. Cyto-
toxic drugs.
Am Rev Respir
Dis 1986;
133:321-340.
Engl J Med 1986; 314:834-844. Mark EJ, Ramirez JF. Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis. Arch Pathol Lab Med 1985; 109:413-418.
Radiology
709
#{149}
R. Aberle,
MD
#{149} Gordon
Gamsu,
A combination of cytotoxic and corticosteroid therapy has dramatically improved the long-term survival of patients with Wegener granulomatosis. With extended survival, patients now experience diverse cardiopulmonary abnormalities that represent primary or secondary manifestations of the disease or that result from diagnosis and treatment. To evaluate these abnormalities, the authors reviewed the medical histories and chest radiologic findings of 19 patients with the histologic diagnosis of Wegener granulomatosis. In these patients thoracic images demonstrated parenchymal nodules or consolidations with cavitation, diffuse interstitial disease, mediastinal or hilar adenopathy, and isolated stenoses of the larynx or tracheobronchial tree. Intrathoracic relapse occurred in 18 cases; in onethird of these patients, findings at relapse differed from those at initial presentation. Complications from diagnosis or therapy occurred in nine patients. Pulmonary infection was the most frequent complication causing morbidity and was often clinically indistinguishable from the primary disease; it complicated relapse in five patients. The successful radiologic follow-up of patients with Wegener granulomatosis requires a consideration of the varied thoracic manifestations of both the primary disease and the complications of its treatment. Index Lung,
terms: Wegener diseases, 60.622
Radiology
1990;
From
Conte
the
accepted Current c RSNA,
Department
November address: 1990
gramulomatosis,
60.622
#{149}
174:703-709
Ave. Los Angeles,
fornia San Francisco meeting. Received 2
#{149} David
Lynch,
Thoracic Manifestations Granulomatosis: Diagnosis
,
I
MD
of Radiological
Sciences,
CA 90024 (D.R.A.),
W
MD2
of Wegener and Course’
granulomatosis is an idiopathic disease characterized by necrotizing vasculitis and gnanulomatosis. Although recognized as a EGENER
multisystem nant sites pamanasal
disorder, the predomiof involvement are the sinuses, lungs, and kidneys
(1). With the the prognosis matically remission tion (2).
use of cytotoxic of this disease
improved, is now As such,
agents, has dma-
and long-term a realistic expectain patients with
Wegener
granulomatosis, a variety of abnormalities are demonstrated that represent manifescardiopulmonary
tations plications
ment.
of the primary disease or comof its diagnosis or manage-
Early
recognition
abnormalities
of specific
is critical
ate intervention and bidity. To better characterize of thoracic
for
appmopri-
reduced
mom-
the
diversity in this
of California
San
Francis-
co with the histologic diagnosis of Wegener granulomatosis over a 19year period. We compared the dismanifestations with those
SUBJECTS
of this populareported in the litera-
AND
From 1969 to 1988, tologically confirmed matosis
were
seen.
All
cytotoxic
who
METHODS 19 patients Wegener patients
with hisgranulohad
cine
CT
University
Los Angeles,
University
School of Medicine, San Francisco (G.G., DL.). From the 1988 August 30, 1989; revision requested October 2; revision received 14. Address reprint requests to D.R.A. Department of Radiology, University of Colorado, Denver.
cyclophospha-
not
receive
therapy,
shortly
after
one
presen-
scans
(CT) scans (n
(n
1) of the
6), and
upper
airway.
dis-
1. Ten monary nodules
of Radiology,
did
ed tomographic
tions
of California
typically
tation. In the other patient, the diagnosis of Wegener granulomatosis was made only at autopsy. Sixteen patients were followed up at our institution; the duration of follow-up ranged from 1 1 months to 13 years. The mean duration of follow-up was 61 months ± 43 (mean ± standard deviation); the median duration of followup was 48 months. Images demonstrating pulmonary abnormalities at presentation and during follow-up were reviewed for each patient and consisted of chest radiographs (n 19), conventional lung tomograms (n 2), tracheograms (n 1), thoracic comput-
ease involving the paranasal sinuses, the lungs (including isolated or concomitant airway disease), or the kidneys. In 16 patients, two or more of these sites were involved. Intrathoracic involvement with Wegener granulomatosis was present in 18 patients at initial presentation or at
and the Department
agents,
mide. High-dose corticosteroids were given concomitantly, and the dose was tapered to the lowest effective dose. Administration of cytotoxic agents was continued from several months to 1 year after response or remission. Of the two subjects
population, we reviewed the medical records of all patients seen at the
ease tion tune.
point during the course of the disOne subject initially had only cutaneous and renal disease; lesions of the hypopharynx occurred at relapse. In all patients, the diagnosis of Wegener granulomatosis was established from histologic examination of tissues obtained from the lungs or conducting airways (n 11), the nose or paranasal sinuses (n 9), the kidneys (n = 6), the skin (n 4), or the heart (n 1). In 12 patients, representative histologic specimens were present from two sites. Seventeen patients were treated with ease.
was lost to follow-up
manifestations
University
some
10833
Le-
of Cahi-
RSNA annual November 10;
RESULTS Initial The
Pulmonary initial of the
Manifestations
pulmonary disease
are
manifestalisted
in Table
of 19 patients had classic findings of parenchymal (Fig la); in all but one
tient, the nodules were multiple. Nodules were of varying sizesranging from several millimeters
several lateral,
centimeters-were and had no regional
pulpa-
to
usually bidistnibu703
Figure 1. Preliminary chest radiographic findings in three patients with Wegener granulomatosis. (a) Typical presentation of parenchymal nodules, some with cavitation (arrows). Paratracheal and right hilar adenopathy is also present. Adenopathy occurred in three of our patients; however, in none was it an isolated intrathoracic finding. (b) Cavitary air-space consolidation, initially misdiagnosed as infectious pneumonia. (c) Collimated view of the right lower lobe demonstrates prominent reticular and bronchovascular markings bilaterally without focal
masses.
gener
Transbronchial
biopsy
findings
demonstrated
small
vessel
vasculitis
and
sterile
necrotizing
granulomas
characteristic
of We-
granulomatosis.
tion. In seven patients, the nodules were cavitary. Cavitary air-space consolidation (Fig ib) initially thought to represent necrotizing bacterial pneumonia
was
seen
in
two
Table
1
Initial
Parenchymal
the bronchovascuinterstitium was prominent without discrete puimonary nodules (Fig ic). Both patients had multisystem disease involving the paranasal sinuses, kidneys, or
sites.
Results
from
Granulomatosis
in 19 Patients No.
of Patients
findings
14
Nodules
3 7
Cavitary nodules Focal air-space disease
simulating
Increased bronchovascular Airway lesions
Larynx Trachea Main-stem Other
transbron-
chial biopsy in both patients strated necrotizing vasculitis tent with findings in Wegener
of Wegener
Feature
patients.
In two patients lar and peripheral
other
Manifestations
Thoracic
cavitary
pneumonia
2
lines
2 2
2 2 1
(intrathoracic) bronchus
Adenopathy
demonconsisgran-
Mediastinal Hilar Normal chest
3 2 3 3
radiographs
ulomatosis.
Adenopathy tinum
of the
was
In each
present
case
findings
three
adenopathy
conjunction
with ties
hila
in
with and
or mediaspatients.
occurred
other
regressed
the accompanying during the course
intrathoracic
in
changes ration
in
appropriate
concert
abnormaliof cytotoxic
low
Two patients presented with stnidor and/or hoarseness in the absence of pulmonary parenchymal disease. In both endoscopy revealed circumferentiai narrowing of the glottis and infraglottic airway. In one patient, a vocal cord granuloma was found to be the cause of hoarseness, and tracheostomy was performed to bypass the laryngeal obstruction. In the other patient, CT was performed to depict the airway distal to the narrowed larynx (Fig 2). Conventional CT mevealed severe soft-tissue thickening of the larynx and diffuse circumferential narrowing of the trachea and proximal
main-stem
Cine cheal 704
was
bronchi.
irregularly
CT was performed compliance and
Radiology
#{149}
Trache-
calcified. to assess dynamic
tra-
in the was
airways during used to determine
site
the
level
ryngeal
therapy.
al cartilage
and
for
respithe bela-
tracheostomy
of the
most
severe
stenosis.
In three patients, results from the initial chest radiographs were normal. One patient has never developed intrathoracic manifestations of
disease;
the
histologic
diagnosis
Wegener granulomatosis on representative renal
opsy
findings.
tients
with
presentation, way
lesions
In the normal
other
two
radiographs
upper
and
developed
of
was based and nasal bi-
lower
at the
paat air-
time
of
relapse.
lapse
or
despite apy, nosis
or
lung
Pulmonary
Complications
of Disease
Course
tions
of
initial
to diag-
Wegener
2).
six
patients
airway
were
different
pulmonary (eg,
in
one
relapse
each
cavitary
these
was
manifested
without
were
case
the
nodules, was
stenosis
pulmonary
in
patient
manifestation
parenchymal
nodules
from
involvement
pulmonary
whereas
me-
of
(Table
relapse
the
disease). Recurrent
representing
disease
and (c) pulmonary as consequences of disorgan systems without
vasculitis
The pulmonary abnormalities that occurred in the course of disease were of three major types: (a) cardio-
disease
initial
Manifestations of relapse-There were 26 episodes of relapse necessitating hospitalization of the patient or significant alteration of chemotherapy. Of these, 18 relapses involving the lung or airways occurred in 13 patients. Pulmonary manifesta-
cavitary
during
of
pharmacotherrelated
management
granulomatosis, abnormalities ease in other
initial
the
progression
appropriate (b) complications
seen
had
as
parenchymal parenchymal
in
six
been
cases;
the
in
initial
March
1990
were
thought
vaivular
The
to be consistent
Wegenem
patient
was
phosphamide
had
with
granulomatosis.
treated
and
successful
with
cyclo-
conticosteroids
remission
and
of hem pul-
monary
lesions
without
of other
cardiac
abnormalities.
development
Diffuse pulmonary hemorrhage developed in two patients with cavitary pulmonary nodules at initial presentation findings
2.
Images of a 26-year-old man with diffuse wheezing and stridor. At direct laryngoscopy there was severe thickening of the aryepiglottic folds and circumferential narrowing of the larynx; the lower airways could not be depicted, and CT was performed to assess the patency of the tracheobronchial tree. (a) CT scan with soft-tissue window at the level of distal trachea shows circumferential narrowing and soft-tissue thickening with scattered foci of calcification (arrowhead). (b) CT scan with lung window at the level of the main-stem bronchi demonstrates similar soft-tissue thickening (arrows) and narrowing. These changes were continuous with the level of the bronchus intermedius.
Table 2 Thoracic
Complications
during
the Course
of Disease
Feature
No.ofCases __________
18
Cardiopulmonary relapse* Parenchymal nodules Multifocal parenchymal infiltrates Diffuse pulmonary hemorrhage Aortic valvulitis Airway disease Hypopharynx
or other
Pulmonary
7
Superinfection
in preexisting cavities pneumonia Acute alveolar damage (cyclophosphamide-induced) Systemic air embolism after fine-needle aspiration of a vasculitic Extrathoracic relapse Hydrostatic edema secondary to renal failure Diaphragmatic paralysis secondary to phrenic neuropathy *
There
were
18 relapses
among
2 lesion
3 2 1
relapse was insufficiency and progressive tions of the earlier, the resection of per lobe; at was interpreted with sterile
manifested as acute aortic with pulmonary edema cavitary consolidaupper lobes. One year patient had undergone a nodule in the right uphistologic examination it as subacute abscess granulomata. At second
recurrent
admission,
emergency
replacement
was
matosis.
Wegener
granulo-
recurred
sinusitis,
taneous
episclenitis,
or
cu-
vasculitis.
In two chymal
lapse. lobe
of Nodules
patients,
multifocal
consolidations
heralded
In the first, consolidations
withdrawal
of
right and occurred
parenme-
left lower after
cyclophosphamide.
Cavitary pulmonary consolidation had been the initial pulmonary manifestation of Wegener granulomatosis in this patient. In the second patient,
Volume
174
Number
#{149}
3
with
presence rophages
sumed
bacterial
logic
examination
of the
bacterial vegetations. the original lung classic
and
small
identified.
aortic
that
vessel The
valve without
On histologic
features
granulomatosis,
pre-
Histo-
inflammation
review speci-
site
and
of hemosidenin-laden compatible with
bleedthe mac-
diffuse
of treatment presentation.
and
died
2 weeks
lesions occurred in the course of eight
in five parelapses.
debilitating
sites
gallium
activity
tric
granulomata
medius
lapse, tions
focal
at scattered
corresponding seen
at
to the
narrowing
abnormal
of cytotoxic persistent of
right
in all pa-
the
drugs. concen-
bronchus
middle repeated bronchoscopic of granulation tissue and
in-
airway
CT. Therapy
tients consisted one patient with
Wegener
radionuclide
demonstrated
creased
is,
were findings
hoarseness,
patient,
scanning
areas
of
by
cough, stnidor, or reduced exercise tolerance. Chest abnormalities were evident in three patients and consisted of focal or diffuse narrowing of the trachea and main-stem bronchi. In one patient, bronchial narrowing had resulted in right middle lobe collapse. In two patients whose proximal airway disease prevented bronchoscopic evaluation, CT revealed mucosal thickening with on without calcifications at sites of involvement.
of
vasculitis, aortic valve
diffuse
localized
pulmonary hemorrhage. In both patients, acute glomerulopathy occurred concomitantly or within 2 weeks of pulmonary hemorrhage. One patient responded to high-dose corticosteroid and cytotoxic therapy; the second succumbed to complica-
In one
valve
for
endocarditis.
demonstrated
men,
aortic
performed
diffusingIn each patient
revealed no
heralded
13 patients.
while cytotoxic therapy was being tapered or after variable periods of complete disease remission without drug themapy. In each case, symptoms of accelerated disease were found in locations other than the lower respiratory tract and included epistaxis,
manifestation
patients in-
In two patients, airway occlusion had been the initial manifestation of Wegener granulomatosis; in the others, there was either no pulmonary disease at diagnosis (n 2) or initial disease was confined to the pulmonary parenchyma (n 1). The distribution of airway disease was variable and extended from the hypophanynx to the segmental bronchi. In each case, recurrence was symptomatic and was
Leucopenia-related Unrelated
ing
Airway
9
complications
infection
bronchoscopy
tients
4
Main-stem bronchi Lobar collapse
one patient, single-breath capacity was elevated.
tions after
2 1
Larynx/trachea Treatment-related
3). In both presentation
cluded acute dyspnea, anemia, and hypoxemia without hemoptysis. Chest radiographs revealed diffuse bilateral air-space consolidation. In
b. Figure
(Fig at second
In
inter-
lobe
colresec-
were
Radiology
705
#{149}
unsuccessful in relieving the obstruction, and local radiation therapy was given with limited success. Other pulmonary complications. -In 12 instances, pulmonary complica-
I
I
w-
tions occurred in the course of diagnosis or treatment of Wegener granulomatosis (Table 2). Seven of these
were cases, years
related to infection. pneumonia occurred after initial granulomatosis; pneumonia of initial
gener tients, months
In five several
.;
diagnosis
of Wein two paoccurred within 3 diagnosis and prior
to successful remission. Five of the cases of pneumonia were associated with
..1
relapse.
Two
cases
of pneumonia
were
tem-
3.
4.
poraily related to severe neutropenia due to cyclophosphamide administration. Relapse findings in one patient included rapidly progressive glomerulonephnitis and central nervous system vasculitis with grand mal seizures. Cyclophosphamide had
Figure
been discontinued 1 week earlier because of declining peripheral leucocyte counts. Spiking fevers developed in the patient with diffuse air-
anterior chest consolidation nas aeruginosa. nary infection.
space
and
at the Open
time lung
cystis
interstitial
which
resolved
with
pentamidine therapy and restoration of neutrophil counts. A second patient was given cyclophosphamide for active vasculitis with diffuse pulmonany hemorrhage and renal insufficiency. Severe neutropenia developed, and the patient died of overwhelming Staphylococcus aureus
findings of spiking fevers pharmacologic control of
vasculitis, new acute changes graphs including solidation (Fig
levels
productive cough, seen on chest radioprogressive con4) or new air-fluid
in preexisting
cavities.
Two
or
of
these patients had concurrent paranasal sinus involvement; the pulmonary pathogens were the same as those cultured from the paranasal sinuses, suggesting that the pneumonia represented contamination from the upper airways. In the third patient, pneumonia was temporally melated to fibemoptic bronchoscopy.
In two
instances,
bacterial
pneu-
monia occurred in the absence of active pulmonary involvement by Wegenem granulomatosis. In one, right lower lobe pneumonia developed distal to a focal airway stenosis
706
Radiology
#{149}
of a 59-year-old
woman
with
a 4-year
history
of Wegener
gran-
ulomatosis with sinusitis, episcleritis, cutaneous vasculitis, and cavitary pulmonary infiltrates. At presentation the patient had marked dyspnea, hypoxemia, anemia, and chest radiographic evidence of bilateral consolidations of the middle and lower lobes. The patient died, and at autopsy the lung histologic findings were compatible with diffuse pulmonary capillaritis. (4) Radiograph of a 60-year-old man with sinusitis and chronic cavitary lung nodules secondary to Wegener granulomatosis. The patient had long-standing bacterial colonization
of the paranasal
sinuses. radiograph of the right The patient
He presented
with
demonstrates upper lobe. was treated
increasing
dyspnea
multiple bilateral Sputum and sinus successfully with
caused by Wegener granulomatosis. Poor local clearance mechanisms were thought to contribute to the development of this complication. One patient with recurrent episclenitis and cavitary parenchymal nodules experienced progressive dyspnea while receiving maintenance therapy with cyclophosphamide. Chest radiographs appeared un-
changed,
pneumonia with septicemia. Secondary infection of cavitary nodules occurred in three patients with active Wegener granulomatosis. Supeninfection was suspected from
the clinical after initial
(3) Radiograph
and
cavitary cultures antibiotics
spiking
fevers.
nodules and were positive for intercurrent
Postero-
new cavitary for Pseudomopulmo-
consolidations
of severe neutropenia. biopsy revealed Pneumo-
carinii,
3, 4.
but
high-resolution
CT
scans demonstrated patchy groundglass opacification not evident on plain radiographs (Fig 5). Transbronchial biopsy was performed to exdude intercurrent infection and revealed diffuse alveolar damage typical of cyclophosphamide-induced lung injury. In one patient reported previously (3), a fatal systemic arterial air embolism occurred during percutaneous fine-needle aspiration of a lung lesion.
Air
emboli
were
believed
to
have been introduced by coughing after puncture of diseased pulmonary venules. Three patients developed pulmonary complications related to vasculitis in extrathoracic sites. In two, symptoms of acute dyspnea and hemoptysis developed in temporal relation to progressive renal failure. In both patients, hydrostatic pulmonary edema resolved after hemodialysis and restoration of the normal intravascular volume. In another patient,
diaphragmatic in
the
dysfunction
setting
of
left
neuropathy.
Chronic
lyneuropathy
was
Wegener
occurred
phrenic
nerve
peripheral
po-
a manifestation
granulomatosis
of
in this
pa-
tient.
DISCUSSION Wegener granulomatosis is a disease of unknown cause that was first defined in 1936 (1). It is generally considered a hypersensitivity disorder with granulomatous inflammation,
small
vessel
lonephritis,
vasculitis,
and
vation
the
of circulating
immune
glomeru-
occasional
and
complexes.
A
obser-
deposited limited
form
without renal involvement has also been described (1,2). Prior to effective pharmacotherapy, death typically
resulted
from
renal
failure
after
an
average of 5 months, and fewer than 10% of patients survived 2 years after diagnosis (2). The routine administration of cytotoxic agents, particularly cyclophosphamide, conjunction
effected
long-term
majority
of
continued
complete ing
the
tative
generally
histologic
has
remission at
in the
Therapy least
remission, exposure
or in
corticosteroids,
patients. for
toxic side effects The diagnosis matosis
alone
with
thus of
is often
1 year
after
lengthen-
patients
to
the
of these agents. of Wegener granulorequires
findings
represen-
from
March
one
or
1990
b. Figure 5. Images of a 56-year-old for over 7 years. At presentation phamide-induced py there was
nodules plained from
acute paradoxic
(arrows) dyspnea the
lower
alveolar motion
correspond and showed lobes
woman with multisystem she had increasing exertional damage. of the left
to sites patchy
revealed
diffuse
(a) Frontal hemidiaphragm,
of involvement ground-glass alveolar
more sites of involvement. Pathologic changes from lung biopsy specimens are the most conclusive, since findings from other sites such as the upper respiratory tract or kidneys may be nonspecific. Recently, the presence of anticytoplasmic autoantibodies in the serum has been found to be highly specific for the diagnosis
of Wegener rum titers
granulomatosis,
and
se-
vary in response to disease activity (4). However, at present, the finding of anticytoplasmic autoantibodies is not uniformly considered an alternative to a histologic diagnosis. Generally, the pathologic diagnosis requires biopsy, typically by means of open thoracotomy. Percutaneous cytologic sampling under radiologic guidance does not provide sufficient material to demonstrate the histologic changes and may be complicated by uncontrolled hemoptysis, coughing, as occurred However, termining
or systemic air embolism in one of our patients. CT may play a role in dethe optimum site for biopsy by defining those sites in which necrosis has not occurred. The lower respiratory tract manifestations of Wegener granulomatosis are protean. Pulmonary parenchymal features were the first to be descnibed (5-9). Of these, cavitary nodules that may be transient and recurrent (5,8) are the classic and most common pattern of intrathoracic disease. Segmental or lobar consolida-
Volume
174
Number
#{149}
3
chest
involvement dyspnea
radiograph presumed
by Wegener opacification
damage
by Wegener was found
demonstrates to represent
granulomatosis controlled with to have left phrenic neuropathy
new phrenic
elevation neuropathy
with
CT was performed lobes. Transbronchial
cyclophosphamide-induced
radiographically from pneumonia described (8,10).
lung
been
nodular
tients
with
or reticulonodular interstitial temns may occur (9). In most parenchymal involvement,
patcases of histologic
(16).
One-half
tients
have
voice
change,
examination
lung
some,
upper
of our
patients,
of the
diffuse
affected
me-
veals necrotizing granulomata with vasculitis. Diffuse pulmonary hemorrhage is a serious, typically fulminant manifestation of lower respiratory involvement (11-13). Pathologic examination of the lung reveals extensive vasculitis of small arteries, veins, and capillaries; granulomatous changes may be inconspicuous or absent, and there is no consistent immunofluorescent pattern of immune
complex
deposition
(14,15).
In many
of the reported cases of pulmonary hemorrhage with Wegenem gmanuiomatosis, concurrent renal failure has been present, which may result in the erroneous diagnosis of Goodpasture disease despite the absence of demonstrable antiglomerular basement membrane antibody. The airway manifestations of Wegener granulomatosis have received increasing attention over time. This probably reflects both a heightened awareness of the disease as well as an increased frequency due to extended survival of treated patients. The frequency of airway disease is difficult to estimate because most derived from retrospective
reports case
are stud-
At fluoroscoparenchymal
to evaluate unexbiopsy specimens
disease.
indishave As with
two
are
cyclophosphamide as well as cyclophos-
of the left hemidiaphragm. from vasculitis. Small
granulomatosis. (b) High-resolution bilaterally in the middle and lower
compatible
tions that tinguishable also been
and
ies with poor tion. Laryngeal
pathologic involvement
described
documentahas
in up to 25% of paWegener
granulomatosis
or more
of affected
symptoms
pa-
of hoarseness,
or dyspnea airway
(16,17).
stenosis
tates tmacheostomy, two patients in our
In
necessi-
as occurred in series. Lesions
usually affect the subglottic larynx, less often affect the true vocal cords
or epiglottis,
and
may
be ulcerative
or proliferative (16). Histologic mens may show only granulomas without vasculitis (18); in these the diagnosis can be established
disease such neys,
in other as the lung or paranasal
specicases, from
characteristic
areas,
pamenchyma, sinuses.
kid-
Subacute or chronic tmacheobronchial involvement (10,19-22) may
me-
suit in lobar collapse or obstructive symptoms. Disease may be unifocal or multifocal and may involve short or long segments of the intrathomacic trachea and main-stem bronchi. CT can be used to define precisely the site (or sites) of airway involvement, the severity of narrowing, and both intraand extraluminal soft-tissue components. In some of our patients,
severe
upper
airway
stenosis
pre-
cluded bronchoscopic evaluation of the lower respiratory tract, and CT was pivotal in characterizing widespread narrowing of the tmacheobronchial tree. CT can also serve as
Radiology
707
#{149}
the preoperative map for proposed tnacheostomy or bronchoplastic procedures and may obviate more invasive imaging studies such as tmacheobronchography. Cine CT, performed in one of our patients, extends the usefulness of CT by demonstrating dynamic airway changes in response to respiratory maneuvers (21). Cyclophosphamide therapy has a variable effect on airway disease. In our experience, parenchymal lesions in Wegenem gmanulomatosis were more responsive to treatment than were airway obstructions. Some patients experience symptomatic improvement without an appreciable change in cross-sectional measures of obstruction or abnormalities on flow volume loops. In others bronchoplasty, sleeve resection of involved bronchi, or local radiation therapy have been attempted (19). The frequency of relapse and the propensity of this disease to recur in different sites has been proposed as a reason for the limited success of surgical mepair (17). In addition, some reports indicate that the persistent obstruction may be biologically inactive, consisting of granulation tissue and fibrosis (18). A variety of less common intrathomacic manifestations in Wegener granulomatosis have been reported. Pleural thickening, effusions (7,10), and, rarely, hydropneumothorax (10,23) have been described. Mediastinal or hilar adenopathy occurs infrequently (8,24), typically with other pulmonary manifestations of disease, and is thought to represent reactive hyperplasia in the setting of an active inflammatory process. To our knowledge, phrenic nerve neuropathy resulting in diaphragm dysfunction has not previously been meported, although peripheral monoand polyneuropathy are well known consequences of Wegener granulomatosis (5). There have been several reports of cardiac lesions in patients with Wegener granulomatosis (1,5,19). Necrotizing coronary vasculitis and pancarditis are most frequent; isolated valvular lesions, granulomatous inflammation of the epicandium, focal myocardial necrosis, penicarditis, and endocardial mural thrombi have also been described. Patients may develop refractory arrhythmias, congestive cardiomyopathy, or acute pulmonary edema, as occurred in one of our patients. The morbidity in patients with cardiac involvement is high. Finally, pulmonary edema may complicate cases with renal involvement in 708
Radiology
#{149}
the absence of active cardiopulmonary disease. Any of the pulmonary manifestations of Wegenem granulomatosis may occur at initial presentation or at relapse. As well, the pattern of disease expression in the individual patient may vary from one episode to another. In our experience, symptoms were most conspicuous in patients with airway disease or diffuse pulmonary hemorrhage and included fever, hemoptysis, dyspnea, or stnidor. In patients with cavitary masses or nodules, the onset of active disease was typically heralded by symptoms in locations other than the lung, such as the upper respiratory tract or nervous system. In many instances, relapse occurred in the setting of tapering cytotoxic therapy as has been previously reported (2). Given the protean manifestations and chronicity of Wegener granulomatosis,
primary
difficult cations tion.
disease
may
be
to distinguish from compliof therapy or secondary infecIn patients
with
upper
respira-
tory tract symptoms, secondary infection of the paranasal sinuses is more common than relapse of the primary disease (2). Interestingly, in two of our patients with bacterial pneumonia, the same organisms were responsible for chronic, smoldering pamanasal sinus infections. These patients may have developed intercurrent pneumonias by means of contamination from the upper respiratory tract. The frequency of pulmonary infection
in our
patients
was
comparable
to that described by others (25). Patients with pneumonia frequently have fever, pulmonary symptoms, and elevations of erythrocyte sedimentation rate comparable to findings at relapse. Furthermore, in the lower respiratory
tract
relapse may be
complicated by intercurrent pulmonary infection (25) and occurred in five of our patients. Radiographic changes such as increasing consolidation or the development of aim-fluid levels within cavities are not specific but may reflect intercurrent infection. An association between relapse and infection has been described in a prospective, longitudinal study of patients with Wegenem granulomatosis
by
Pinching
et al (25).
Among
18
patients, nine of 20 relapses were associated with intercurrent infections. Funthenmore, the site of infection appeared to determine the site of melapse; of six respiratory infections, all were associated with pulmonary relapse. In their study (25), successful
treatment generally required treatment of the infection as well as escalation of immunosuppressive therapy. The authors contended that infection may precipitate relapse through
reactivation of infection-derived cmculating immune complexes, or that the acute-phase or cellular response to infection may enhance quiescent disease. Given the apparent association
between
relapse
and
infection
and the similarity of their symptoms, chest radiographic evaluation for infection is indicated for any increase in systemic or pulmonary symptoms and during the tapering of cytotoxic drugs or corticostemoids in patients with known lower respiratory tract
involvement. Cytotoxic
treatment
granulomatosis
has
once
almost
into one remission
of Wegenem transformed
uniformly
a
fatal
disease
with potential for long-term or cure. Active vasculitis
of
the central nervous system, kidneys, and lungs may be fulminant, and the delay of appropriate cytotoxic therapy in these cases has been implicated as a major cause of morbidity (2,5). However, the potential side effects of cytotoxic agents place patients at risk for a variety of complications. Semious infection resulting from cyclophosphamide-induced immune suppmession occurred in two of our pa-
tients.
In addition,
undiagnosed istration
sumed
in patients
relapse
Drug-related interstitial
could
be catastrophic.
alveolar fibrosis are
damage known
ae of cyclophosphamide tion
with
pneumonia, the adminof cytotoxic agents for pre-
(26)
but
and sequel-
administra-
may
be
difficult
to ap-
preciate on chest radiographs in the presence of pulmonary pamenchymal vasculitis. In one of our patients with progressive dyspnea and stable chest radiographs, high-resolution CT was performed to better evaluate parenchyma. Unsuspected ings prompted biopsy and tion of drug-induced lung
the lung CT findconfirmainjury.
The intrathomacic manifestations of Wegenem granulomatosis are multipie and varied. Parenchymal involvement is the most typical expression
of disease;
rience
however,
isolated
stenoses
are
in our
or concomitant common.
expe-
airway
Cardiac
in-
volvement has also been reported to occur in up to 30% of patients. In the individual
relapse tial
vival,
patient,
often
manifestations
differ
presentation.
a variety
plications may as the consequence
involvement;
from With
of
those
at
extended
sum-
of intrathoracic result
these
corn-
from therapy of extrathoracic
may
mi-
have
or
pro-
March
1990
found impact on the course of the disease on may be confused with pnimary lower respiratory tract involvement. Pulmonary infection is the most frequent and potentially serious complication, since the failure to necognize infections can have serious consequences in patients receiving immunosuppressive therapy. Thomacic imaging plays a key role in the evaluation and monitoring of patients with Wegenem granulomatosis.
Successful
madiologic
plasmic
Wolff SM, Fauci AS, Horn RG, Dale DC. Wegener’s granulomatosis. Ann Intern Med 1974; 81:513-525. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with for
21 years.
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in
their
16.
17.
immuno-
Wegener
granuloma-
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studies
in eighteen
patients
review of the literature. 52:535-561. McGregor MBB, SandIer
and
Medicine G.
18. a
1973;
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granulomatosis: 7.
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Br
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L, Van
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HS.
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AJR
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Gohel VK, Dalinka MK, Israel HL, Libshitz HI. The radiological manifestations of Wegener’s granulomatosis. Br J Radiol 1973; 46:427-432. Landman 5, Burgener F. Pulmonary
manifestations 10.
Ordstrand
granulomatosis:
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granuloma-
122:750-757.
R, Fauci AS, Doppman
SM. Unusual radiographic Wegener’s granulomatosis.
JL, Wolff
22.
features of AJR 1978;
130:233-238. 1 1.
12.
Hensley MJ, Feldman NT, Lazarus Galvanek EG. Diffuse pulmonary rhage and rapidly progressive renal ure: an uncommon presentation of gener’s granulomatosis. Am J Med 66:894-898.
Albelda
SM, Gefter
DM,
pulmonary classification.
Stokes
BG, Rees RT, Sims EH,
TC, McCann
Grupe WE, Colvin year-old boy wtih
Thorax
1982;
CA.
Wegener’s
granulomatosis:
a
radiological review of the pulmonary manifestations at initial presentation and during relapse. Clin Radiol 1982; 33:545551. Stein MG, Gamsu G, Webb WR, Stulbarg MS. Computed tomography of diffuse tracheal stenosis in Wegener granulomatosis. J Comput Assist Tomogr 1986; 10:868-870. Cohen MI, Gore RM, August CZ, Ossoff RH. Tracheal and bronchial stenosis associated with mediastinal adenopathy in Wegener granulomatosis: CT findings. J Comput Assist Tomogr 1984; 8:327-329. Epstein DM, Cefter WB, Miller WT, Cohel V, Bonavita JA. Spontaneous pneumoan
uncommon
manifestation
granulomatosis.
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1980;
135:327-328. 24.
Nichols L. A 31-year-old woman with cough, hemoptysis, and bilateral hilar adenopathy. JAMA 1983; 249:2691-2692. Pinching AJ, Rees AJ, Pussell BA, Lockwood CM, Mitchison RS, Peters DK. Re-
lapses
37:315-316.
EJ. A 15and occult
Farelly
thorax:
fulminating intrain Wegener’s
RB, Mark hemoptysis
Thomas K. Laryngeal manifestations of Wegener’s granuloma. J Laryngol Otol 1970; 84:101-106. McDonald TJ, Neel HB, DeRemee BA. Wegener’s granulomatosis of the subglottis and the upper portion of the trachea. Ann Otol Rhinol Laryngol 1982; 91:588592. Talerman A, Wright D. Laryngeal obstruction due to Wegener’s granulomatosis. Arch Otolaryngol 1972; 96:376-379. Flye MW, Mundinger GH, Fauci AS. Diagnostic and therapeutic aspects of the surgical approach to Wegener’s granulomatosis. J Thorac Cardiovasc Surg 1979; 77:331-337.
Wegener
hemorR.adiol-
blood in the urine. Massachusetts General Hospital Case Records, case 12-1986. N
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BDW. Acute haemorrhage
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Miller WT. Diffuse rhage: a review and ogy 1985; 154:289-297. Harrison pulmonary
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13.
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Aberle DR, Gamsu G, Goldon JA. Fatal systemic arterial air embolism following lung needle aspiration. Radiology 1987; 165:351-353. N#{246}lleB, Specks U, L#{252}demann J, Rohrbach MS. DeRemee RA, Gross WL. Anticyto-
survey.
References
2.
4.
evaluation
requires familiarity with the myriad intmathomacic manifestations of the disease, knowledge of the potential for other associated complications, and careful correlation of findings with patient symptoms and treatment. CT can accurately help confirm the presence and extent of airway involvement, particularly in patients for whom upper respiratory tract obstruction precludes direct endoscopy, and is an important adjunct in the surgical planning of bronchoplastic or other corrective procedures. Finally, imaging guidance may be useful to determine appropriate sites for biopsy to provide histologic or microbiologic analysis. U
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3.
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