Semiinvasive Pulmonary

Aspergillosis in Chronic
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Obstructive Pulmonary Disease:

Radiologic and Pathologic Findings in
Nine Patients
Toms Franquet 1 OBJECTIVE. The purpose of this study is to assess the radiographic, thin-section CT, and
Nestor L. Mller 2 histologic findings of semiinvasive aspergillosis in patients with chronic obstructive pulmo-
Ana Gimnez 1 nary disease (COPD).
Pere Domingo 3 MATERIALS AND METHODS. The study included nine patients with COPD seen at
the Hospital de Sant Pau during a 3-year period who had histopathologically proven as-
Vicente Plaza 3
pergillosis with tissue invasion. Chest radiography and thin-section (2-mm collimation) CT of
Ramn Bordes 4
the chest were available in all cases.
RESULTS. Nine patients had semiinvasive aspergillosis proven at autopsy (n = 7) or by thora-
coscopically guided lung biopsy (n = 2). The radiologic findings consisted of parenchymal con-
solidation (n = 6) and nodules larger than 1 cm in diameter (n = 3). Parenchymal consolidation
involved the upper lobes in five patients and was bilateral in four. Cavitation was present in two of
the patients with consolidation and in two of the patients with nodular opacities. Adjacent pleural
thickening was revealed by CT in four patients. Histologically, the areas of consolidation repre-
sented active inflammation and intraalveolar hemorrhage containing Aspergillus organisms. In
the three patients with multiple cavitated nodules, a variable degree of central necrosis was ob-
served. The inflammatory infiltrate extended into the surrounding lung parenchyma, and adjacent
areas of hemorrhage were also seen. Aspergillus colonies were identified within the lung tissue.
CONCLUSION. Upper lobe consolidation or multiple nodules in patients with COPD
should raise the possibility of semiinvasive aspergillosis.

Received April 7, 1999; accepted after revision
June 21, 1999.
1
Department of Radiology, Hospital de Sant Pau,
Universidad Autnoma de Barcelona, San Antonio M.
Claret 167, 08025, Barcelona, Spain. Address
correspondence to T. Franquet.
2
Department of Radiology, University of British Columbia
and Vancouver Hospital and Health Sciences Centre,
855 W. 12th Ave., Vancouver, British Columbia, V5Z 1M9
Canada.
3
Department of Internal Medicine, Hospital de Sant Pau,
Universidad Autnoma de Barcelona, 08025, Barcelona,
Spain.
4
Department of Pathology, Hospital de Sant Pau,
Universidad Autnoma de Barcelona, 08025, Barcelona,
Spain.
AJR 2000;174:5156
0361-803X/00/174151
American Roentgen Ray Society
M
ost pulmonary diseases caused by
Aspergillus have been categorized
as invasive, saprophytic, or allergic
[1, 2]. However, semiinvasive aspergillosis, also
called chronic necrotizing aspergillosis, has re-
cently been recognized as a different type of in-
fection that does not fit into the three traditional
categories [3, 4]. Although invasive forms of as-
pergillosis involve previously healthy areas of
lung as a complication of an immunosup-
pressed state [5, 6], semiinvasive aspergillosis is
more indolent and tends to occur in patients
who have mildly impaired immunity due to
chronic debilitating illness, advanced age, or
prolonged corticosteroid administration, or in
patients with underlying bronchiectasis or
chronic obstructive pulmonary disease (COPD)
[3, 4, 79]. Some studies suggest that semiinva-
sive aspergillosis is increasing in frequency and
may be severe or fatal if untreated [8, 9].
The radiographic appearance of semiinvasive
pulmonary aspergillosis has been described as
consisting mainly of upper lobe consolidation and
pleural thickening, and may be indistinguishable
from pulmonary tuberculosis [3, 4].
Limited information is available about the
CT findings and the histologic basis for the ra-
diologic abnormalities. Respiratory infection
is an important cause of morbidity and mortal-
ity in patients with COPD. Accurate diagnostic
evaluation and familiarity with the radiologic
manifestations of semiinvasive aspergillosis is
necessary to guide proper therapy and improve
patient survival [10].
The purpose of the present study was to eval-
uate the radiographic and thin-section CT find-
ings of semiinvasive pulmonary aspergillosis
infection in patients with COPD and to compare
the radiologic with the histologic findings.
Materials and Methods
Patients
From January 1995 through July 1998, all pa-
tients with COPD and pathologic evidence of semi-
invasive pulmonary aspergillosis were identified by
a review of the pathology database records in the

AJR:174, January 2000 51


department of pathology at the Hospital de Sant Pau.
The records of nine smokers with COPD and a
pathologically proven diagnosis of semiinvasive as-
pergillosis were reviewed. Semiinvasive aspergillo-
sis was diagnosed at autopsy in seven patients and
by thoracoscopically guided biopsy in two patients.
All patients had undergone both conventional chest
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radiography and CT. The patients were all men with
a mean age of 68 years (range, 5489 years).
Imaging Technique
All CT examinations were performed with a
Toshiba 900 CT unit (Toshiba Medical Systems, To-
kyo, Japan). Thin-collimation (2-mm) sections were
obtained at 10-mm intervals extending from the lung
apices to below the costophrenic angles. A 35-cm
field of view and a 512 512 reconstruction matrix
were used. Images were reconstructed with a
high-spatial-frequency algorithm for parenchymal
analysis and with a standard algorithm for mediasti-
nal evaluation. CT scans were obtained at the sus-
pended end-inspiratory volume with an imaging
52
Franquet et al.
time of 2 sec. All images were obtained at window
levels appropriate for lung parenchyma (window
width, 1700 H; window level, 600 H) and mediasti-
num (window width, 350 H; window level, 50 H).
Review of the Images
Chest radiographs and CT scans were indepen-
dently evaluated by two chest radiologists, and the
interpretation was reached by consensus only when
discrepancies were identified. The conventional
chest radiographs and the corresponding CT images
were reviewed. Conventional chest radiographs and
CT scans were analyzed for the presence of paren-
chymal consolidation, cavitation, nodules, pleural
thickening or fluid, bronchiectasis, and any other
significant finding. The distribution of lesions was
recorded as predominantly in the upper, middle, or
lower lung zone, and as predominantly central, pe-
ripheral, or random.
Histopathologic diagnosis was based on histo-
logic findings of Aspergillus colonies in the bron-
chial tree and lung parenchyma.
A B
Results
Most patients (n = 7) had COPD of the
chronic bronchitis type, whereas two had centri-
lobular emphysema affecting predominantly
the upper lobes. Five patients had received
low-dose corticosteroid treatment for COPD.
Six patients had received antibiotics for sus-
pected pulmonary infection that was not respon-
sive to therapy. Three patients were alcoholics,
one had diabetes, and one had chronic renal in-
sufficiency. Symptoms and signs at presentation
included cough (eight patients, 89%), sputum
(seven patients, 78%), fever (six patients, 67%),
shortness of breath (five patients, 56%), and he-
moptysis (two patients, 22%). Histologic and
microbiologic proof of semiinvasive aspergillo-
sis was obtained from specimens taken at au-
topsy (n = 7) or at thoracoscopically guided
biopsy (n = 2). Before death, all the patients had
received a diagnosis of probable semiinvasive
Fig. 1.Semiinvasive pulmonary
aspergillosis in 72-year-old man
with centrilobular emphysema and
2-month history of cough and chest
discomfort at presentation.
A, Posteroanterior chest radiograph
shows peripheral and right apical
air-space consolidation.
B, CT scan obtained at same level as A
shows segmental air-space consolida-
tion in posterior segment of right upper
lobe that contains multiple low-attenu-
ation areas (arrowheads), small air
bubbles, and punctate calcifications.
C, Photomicrograph of biopsy speci-
men obtained from right upper lobe
reveals widespread intraalveolar exu-
dative eosinophil material mixed with
acute inflammatory cells, macro-
phages, and fungal hyphae (straight
arrows). Microabscess containing As-
pergillus fumigatus colonies (curved
arrows) corresponds to low-attenua-
tion areas seen on B. (H and E, 400)
C
AJR:174, January 2000
 Semiinvasive Pulmonary Aspergillosis

aspergillosis based on clinical, microbiologic,
and radiologic criteria [3, 7].
On conventional chest radiographs, areas
of consolidation were identified in six pa-
tients; the areas were multiple and bilateral
in four and focal in two. The consolidation
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was located predominantly or exclusively in
the upper lobes in five patients. Areas of cav-
itation were present in two patients. Multiple
pulmonary nodules measuring greater than 1
cm in diameter without associated halos of
ground-glass attenuation were present in
three patients; multiple cavities were identi-
fied in two patients. Other findings included
pleural thickening in four patients and myce-
tomas seen on radiography in one patient.
On CT, the areas of consolidation were
shown to be segmental in all six patients. Ad-
jacent pleural thickening was identified on

CT in four patients (Fig. 1). Cavities seen in

two patients with consolidation had irregular
walls and ranged in size from 1 to 4 cm (Fig.
2). The multiple nodular opacities present on
CT in three patients had ill-defined margins.
Multiple cavitations were seen in two patients
with nodules. Mycetomas were identified on
CT in two patients (Fig. 3).
Histologic examination in the six patients
with parenchymal consolidation on radiogra-
phy and CT showed Aspergillus organisms in
alveolar spaces, intraalveolar hemorrhage,
active inflammation, and tissue necrosis with
microabscess formation (Fig. 4). In the three
patients with multiple cavitated nodules, a
variable degree of central necrosis was ob-
served. The inflammatory infiltrate extended
into the surrounding lung parenchyma, and
adjacent areas of hemorrhage were also seen.
Aspergillus colonies were identified within
the lung tissue. Culture confirmation of As-
A B
pergillus fumigatus was obtained in all nine
patients. In one patient, Aspergillus hyphae
were also found in the liver and the gas-
trointestinal tract.

Discussion
Aspergillus organisms are ubiquitous and
are part of the normal environmental flora
that abound in the soil around us. Although
all human beings are commonly exposed to
these organisms, disseminated and invasive
forms of aspergillosis can occur in immuno-
logically compromised hosts [15, 1114].
In severely immunocompromised pa-
tients, invasive pulmonary aspergillosis can
develop [5, 6]. Predisposing factors for the
semiinvasive form of pulmonary aspergillosis
include mildly impaired host immunity and
underlying lung disease. Semiinvasive as-
pergillosis, or chronic necrotizing asper-
gillosis, has radiologic manifestations distinct
C from those of classic invasive aspergillosis [3,
7]. Conditions associated with the develop-
Fig. 2.Semiinvasive aspergillosis in 68-year-old man with chronic bronchitis and recurrent episodes of mild hemoptysis.
A, Thin-section (2-mm collimation) CT scan obtained with lung windows shows rounded area of consolidation
ment of semiinvasive pulmonary aspergillosis
with associated cavitation in left upper lobe. include chronic debilitating illness, diabetes
B, Photograph of left upper lobe pathologic specimen from autopsy shows irregular cavitary lesion with regular mellitus, malnutrition, alcoholism, advanced
margins and dark-brown appearance, consisting of necrotic material and Aspergillus organisms. age, prolonged corticosteroid administration,
C, Photomicrograph of pathologic specimen shows cavitary lesion containing fungal septate hyphae branching
at an acute angle, which is morphologically consistent with aspergillosis. Wall of abscess shows mild inflamma- and chronic obstructive lung disease [3, 7-9].
tory reaction. Surrounding pulmonary parenchyma is healthy. (H and E, 400) Clinical symptoms are often insidious and

AJR:174, January 2000 53

 Franquet et al.
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A B

Fig. 3.Multiple bilateral nodules and cavitary aspergillosis in

left upper lobe in 54-year-old man with chronic bronchitis and
recurrent episodes of hemoptysis.
A, Posteroanterior chest radiograph shows multiple nodular
opacities in left lung (straight arrows); paramediastinal ill-de-
fined density is also visible (curved arrow ).
B, Thin-section CT scan confirms presence of bilateral,
multiple, ill-defined nodules of various sizes. Cavitation
with presence of air crescent, not seen on conventional
radiography, was easily shown by CT.
C, Patient died 4 months after CT examination shown in B.
At autopsy, aspergillosis abscesses and multiple small
bronchial and bronchiolar yellowish nodules correspond-
ing to fungal bronchitis were found. Photomicrograph
shows massive Aspergillus hyphae invading bronchial and
bronchiolar epithelium (arrows). (H and E, 400)
C

54 AJR:174, January 2000

 Semiinvasive Pulmonary Aspergillosis

Fig. 4.Semiinvasive pulmonary aspergillo-

sis in 56-year-old man with chronic bronchitis
and history of tuberculosis.
A, Posteroanterior chest radiograph obtained 6
months before presentation shows chronic bi-
lateral upper lobe infiltrates with associated
calcified granulomas consistent with previous
tuberculosis (arrows). Perihilar irregular linear
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opacities are also seen.

B, Posteroanterior chest radiograph obtained
at time of presentation shows significant pro-
gression of upper lobe infiltrates.
C, Thin-section CT scan at level of upper lobes
shows bilateral parenchymal consolidation in
both upper lobes.
D, Postmortem microscopic examination con-
firmed fungal infection caused by Aspergillus
fumigatus. Photomicrograph from small area of
consolidation shows tissue necrosis. Aspergil-
lus hyphae (arrows) could be identified in ne-
crotic tissue. (H and E, 400) A B

C D

include chronic cough, sputum production,
fever, and constitutional symptoms (weight
loss and weakness). Hemoptysis is seen in
only 15% of patients.
The diagnosis is often difficult to make be-
cause Aspergillus organisms may be present in
the sputum or bronchoalveolar lavage fluid in
patients who have colonization of the airways
without tissue invasion [15, 16]. In clinical
practice, the diagnosis of semiinvasive as-
pergillosis is usually based on the presence of
multiple cultures positive for Aspergillus or-
ganisms, chest radiographs with abnormal
findings, and bronchoscopy biopsy specimens
consistent with tissue invasion.
In patients with COPD, semiinvasive as-
pergillosis may present with a variety of
nonspecific clinical symptoms such as
cough, sputum production, and fever for
more than 6 months. The slow progression
of clinical and radiographic findings (several
months to years) may contribute to a delay
in diagnosis [3, 4, 7].
Despite the relatively nonspecific appear-
ance on imaging, unilateral or bilateral pa-
renchymal opacities in the upper lung zones
are the most common radiographic findings
in patients with COPD and semiinvasive as-
pergillosis. This upper lobe predominance
may be related to the fact that underlying
diseased areas of lung promotes this form
of infection. The findings are similar to
those seen with tuberculosis. In COPD pa-
tients with semiinvasive aspergillosis, a
high prevalence of cavitation, occurring in
53% of lesions, was observed. CT scans
provide accurate information about the ex-
tent and distribution of these cavities and
about the associated pleural thickening. The
treatment of this form of aspergillosis re-
mains controversial; however, good results
have been obtained in symptomatic patients
using IV amphotericin B, oral itraconazole,
or both.
In conclusion, unilateral or bilateral seg-
mental areas of consolidation and multiple
nodular opacities are the most frequent CT
findings of semiinvasive pulmonary asper-
gillosis. These findings are nonspecific,
most commonly mimicking those of reacti-
vation tuberculosis.

AJR:174, January 2000 55


References
1. Greene R. The pulmonary aspergilloses: three
distinct entities or a spectrum of disease. Radiol-
ogy 1981;140:527530
2. Klein DL, Gamsu G. Thoracic manifestations of
aspergillosis. AJR 1980;134:543552
3. Gefter WB, Weingrad TR, Epstein DM, Ochs RH,
Downloaded from www.ajronline.org by 36.78.24.119 on 11/05/14 from IP address 36.78.24.119. Copyright ARRS. For personal use only; all rights reserved
Miller WT. Semi-invasive pulmonary as-
pergillosis. Radiology 1981;140:313321
4. Gefter WB. The spectrum of pulmonary as-
pergillosis. J Thorac Imaging 1992;7:5674
5. Kuhlman JE, Fishman EK, Siegelman SS. Inva-
sive pulmonary aspergillosis in acute leukemia:
characteristic findings on CT, the CT halo sign,
and the role of CT in early diagnosis. Radiology
1985;157:611614
6. Won HJ, Lee KS, Cheon JE, et al. Invasive pul-
monary aspergillosis: prediction at thin section
CT in patients with neutropeniaa prospective
56
Franquet et al.
study. Radiology 1998;208:777782
7. Binder RE, Faling LJ, Pugatch RD, Mahasen C,
Snider GL. Chronic necrotizing pulmonary as-
pergillosis: a discrete clinical entity. Medicine
1982;61:109124
8. George PJM, Boffa PBJ, Naylor CPE, Higenbottam
TW. Necrotizing pulmonary aspergillosis compli-
cating the management of patients with obstructive
airway disease. Thorax 1983;38:478480
9. Pittet D, Huguenin T, Dharan S, et al. Unusual cause of
lethal pulmonary aspergillosis in patients with
COPD. Am J Respir Crit Care Med 1996;154:541544
10. Saraceno JL, Phelps DT, Ferro TJ, Futerfas R,
Schwartz DB. Chronic necrotizing pulmonary as-
pergillosis: approach and management. Chest
1997;112:541548
11. Denning DW, Follansbee SE, Scolaro M, Norris
S, Edelstein H, Stevens DA. Pulmonary as-
pergillosis in the acquired immunodeficiency syn-
drome. N Engl J Med 1991;324:654662
12. Brown MJ, Miller RR, Mller NL. Acute lung dis-
ease in the immunocompromised host: CT and
pathologic findings. Radiology 1994;190:247254
13. Logan PM, Mller NL. CT manifestations of pul-
monary aspergillosis. Crit Rev Diagn Imaging
1996;37:137
14. Aquino SL, Kee ST, Warnock ML, Gamsu G.
Pulmonary aspergillosis: imaging findings with
pathologic correlation. AJR 1994;163:811815
15. Yu VL, Muder RR, Porsattar A. Significance of
isolation of Aspergillus from the respiratory tract
in diagnosis of invasive pulmonary aspergillosis:
results from a three-year prospective study. Am J
Med 1986;81:249254
16. Treger TR, Visscher DW, Bartlett MS, Smith JW.
Diagnosis of pulmonary infection caused by As-
pergillus: usefulness of respiratory cultures. J In-
fect Dis 1985;152:572576
AJR:174, January 2000