Original Paper

Respiration 1995:62:341-347

M von EiJJ*
N. Roosb
Pulmonary Aspergillosis:
R. Schultena
M Hessea Early Diagnosis Improves
M. ZiihlsdorJ51
J. van de L o o a Survival
Departm ents of
* Internal Medicine and
*>Radiology, U niversity o f Munster,
Germany
Abstract
Bronchoscopy obtaining bronchoalveolar lavage (BAL) fluid and bronchial
secretions (BS) and/or high-resolution com puted tomography (CT) of the
lungs were performed in 33 patients with pulm onary aspergillosis from 1987
to 1992. The sensitivity of BAL fluid or BS for detecting histologically proven
fungal disease was 33 and 50%, respectively, whereas positive serologies were
only documented in 8% o f the cases. CT scans contributed to the early diagno­
sis o f opportunistic fungal pneumonia: characteristic CT signs were found in
16 of 19 episodes. The more frequent use of bronchoscopy and CT scans
between 1990 and 1992 compared to 1987-1989 for the differential diagnosis
of new pulmonary infiltrates resulted in earlier appropriate treatm ent. The
average introduction o f intravenous (i.v.) antifungal therapy after the onset of
pneumonia was shifted from 12 to 7 days (p < 0.05). The timely implementa­
tion of i.v. antimycotic therapy had a significant impact on survival. Initiation
Key Words o f antifungal treatm ent later than 10 days after the onset of pneum onia
Aspergillosis resulted in a m ortality of 90%, as opposed to 41% with an earlier start of
Bronchoscopy antimycotics (p < 0.01). The earlier use o f appropriate antifungal therapy in
Bronchoalveolar lavage the second treatm ent period im proved survival from 33 to 50% (NS). Bron­
Bronchial secretion choscopy and high-resolution CT scans are mutually complementary diagnos­
High-resolution computed tic tools and should be performed as early as possible in the course of pneum o­
tomography nia for patients at high risk for aspergillosis.

Introduction lular and/or humoral coagulopathies are frequent in this

Invasive pulmonary aspergillosis is becoming a major
cause of m orbidity and mortality in immunocompro-
mized patients, particularly in patients with severe neu­
tropenia [ 1-4], A critical problem limiting effective thera­
py has been the difficulty in early diagnosis o f pulmonary
aspergillosis [5-7], Clinical and radiographic findings in
the lung are often absent, particularly in patients with
severe neutropenia, when the patients first present [8-11 ].
Bioptic procedures are often contraindicated because cel­
patient population [12].
Formerly, most patients with invasive pulmonary as­
pergillosis succumbed with overall m ortality rates of 7 0-
100% [5-7], Reliable noninvasive diagnostic techniques
have therefore been sought. Serodiagnosis is usually too
slow for these critically ill patients [ 13,14], Bronchoalveo­
lar lavage (BAL) is a safe and available technique for the
differential diagnosis of new pulmonary infiltrates, even
in patients with severe thrombocytopenia, but there is still
little information about its role in invasive fungal diseases

Received: PD Dr. Michael von EifF © 1995 S. Karger AG. Basel

August 11. 1994 University o f M unster 0025-7931/95/0626-0341
Accepted after revision: Albert-Schweitzer-Strasse 33 $ 8.00/0
April 5, 1995 D -48129 M unster (Germany)
 Table 1. Patients’ characteristics
(17 males. 16 females) and clinical features Average Range Median

Age, years 16-73 56

Days o f neutropenia
< 1 ,000/cm ■ ’ 48 15-83 46
< 100/cm3 23 6-54 24
Onset o f pneum onia after neutropenia
< 1,000/cm 3, days 18 1-50 10
D uration o f pneumonia, days 33 4-98 28
Mechanical ventilation (n = 13). days 17 1-52 10
Start o f antimycotic treatm ent, days after
onset o f pneum onia 10 1-43 9
N um ber o f antimycotics (n = 32) 2 1-3 2
Treatm ent days 23 2-75 20
Total drug dosage, g
Amphotericin B (n = 31) 1.05 0.06-2.75 1.05
5-Fluorocytosine (n = 31) 152 2.5-480 130
Liposomal amphotericin B (n = 3) 4.3 0.6-7.6 4.6
Itraconazol (n = 1) 13.6

25 patients had intensive cytostatic treatm ent.

[ 15-17]. High-resolution com puted tomography (CT) has
been advocated for the early diagnosis of opportunistic
fungal pneumonias [ 18-20].
Between January 1987 and December 1992, 33 immu-
nocompromized patients developed invasive pulmonary
aspergillosis in our departm ent. O f these, 32 Aspergillus
infections were diagnosed while the patient was alive, and
treatm ent with antifungals was instituted within 24 h of
the diagnosis.
In all these patients, either bronchoscopy and/or CT of
the lungs were performed for the differential diagnosis of
new pulmonary infiltrates. We present here our experi­
ence with this disease entity, review the clinical features
and diagnostic approach, and discuss the therapeutic
management.
Patients and Methods
The patients’ records and autopsy results were evaluated retro­
spectively. The following param eters were analysed in addition to the
clinical courses: (1) histological exam ination o f tissue collected in
vivo and/or postmortem; (2) conventional chest radiographs and CT
scans o f the thorax; (3) microbiological findings in bronchoscopic
specimens, and (4) Aspergillus IgM antibody titres (Aspergillus-HA
test. Roche*) and surveillance cultures.
C T Scan
CT scans were performed on a Philips-Tomoscan 350-Scanner.
In all cases, scans were obtained at 0.9-cm intervals using 0.9-cm
collimation. The lungs were viewed and photographed at a level of
600-700 Hounsfield units (H) and at a window width o f 1,000-
1,200 H. For the m ediastinum , a window level between 40 and 60 H
and a window width between 300 and 500 H were used.
BAL Studies
For BAL, a bronchoscope was advanced and wedged into a seg­
mental bronchus supplying an area of radiographic abnormality.
Alveolar lavage was performed by the sequential instillation and suc-
tioning o f 50-ml volumes of sterile physiologic saline. The procedure
was repeated four times, and the fluid returns pooled. An aliquot of
BAL fluid served for culture o f aerobic bacteria, Legionella, myco­
bacteria. fungi and viruses. Cytopreparation smears were routinely
stained with Grocott for detection o f Pneumocystis carinii and fungal
organisms, gram stain for bacteria and auram ine-rhodam ine for
mycobacteria. Assays for Legionella and for cytomegalovirus used
direct immunofluorescence. Papanicolaou stains were examined for
the presence o f malignant cells, intracytoplasm atic or intranuclear
viral inclusion bodies and hemosiderin-loaden macrophages. Bron­
chial secretions (BS) were suctioned via the working channel o f the
bronchoscope and examined for bacteria, fungi, mycobacteria and
Legionella.
Diagnostic Criteria
A diagnosis o f aspergillosis was either established by histological
demonstration o f pulmonary invasive disease or, in patients with
clinically documented infections, Aspergillus spp. were cultured in
respiratory secretions and, additionally, characteristic radiographic
patterns, positive serological results or clinical and/or radiological
response after starting intravenous (i.v.) antifungal treatm ent were
documented. The CT criteria for an invasive pulmonary aspergillosis
(IPA) were angiotropic nodular parenchymal lesions (>0.5 cm) with
or w ithout the accompanying so-called ‘halo-sign’ and/or wedge-
shaped. pleura-based infiltrates [ 18-20].
Statistical A nalysis
For statistical analysis, %2 and Student’s t tests were used.

342 von Eiff/Roos/Schulten/Hesse/Ziihlsdorf/ Early Diagnosis o f Pulmonary Aspergillosis

van de Loo
 Results Table 2. Underlying diseases

Num ber
Aspergillosis was diagnosed in 15 cases histopathologi-
cally. In the other 18 cases, Aspergillus spp. were cultured Acute myelogenous leukaemia 13
16 times from BAL fluid and/or BS and twice from sputum. Acute lymphoblastic leukaemia 3
Additionally, characteristic signs o f aspergillosis in high- Chronic lymphocytic leukaemia 3
resolution CT (n = 10), significant anti-Aspergillus anti­ Chronic myelogenous leukaemia 2
Non-Hodgkin's lymphoma 5
bodies (n = 3) and clinical and/or radiological response after
Agranulocytosis 1
starting antifungal treatment (n = 11) were demonstrated. Non-small cell lung cancer 1
The patient's characteristics are given in table 1. The Kidney transplantation 3
majority o f patients had haematologic malignancies (ta­ Moschcowitz’ disease 1
ble 2). 25 patients had received intensive cytostatic treat­ W aterhouse-Friderichsen syndrome 1
ment and had subsequently developed severe neutropenia
and thrombocytopenia. 17 patients were pretreated with
steroids (>20 mg prednisone daily for > 2 weeks). 3
patients had additionally been treated with cyclosporin A
for more than half a year. All patients had fever refractory Table 3. Microbiologic findings in BAL
to broad spectrum antibiotic therapy. On average, tem ­ fluid and BS (n = 28)

peratures elevated above 38.4°C were docum ented for 19

BAL BS
days (range 4-62). 8 different antibiotics were given for 4
up to 102 (average 34) days. Some patients had two or Aspergillus species 14 21
more episodes o f fever during hospitalization; the first Candida species 6 8
bout of fever, usually responsive to antibiotic therapy, Pneumocystis carinii 1 -
was followed by a second persistent febrile episode. I.v. Cytomegalovirus 1 -
antimycotics were started on average 10 days after the Proteus mirabilis - 1
onset o f pneum onia with documented pulmonary infil­ Pseudomonas aeruginosa 2 3
trates and/or elevated body tem perature above 38.4°C. Legionella pneumophila 3 2
31 patients were treated with a com bination of am photer­ Staphylococcus aureus 2 1
icin B and 5-fluorocytosine i.v. for 23 days (range 2-57), 1 Staphylococcus epidermidis 9 10
patient was treated with itraconazol. 3 patients originally Streptococcus riridans 2 4
Enterococcus species 2 1
treated with amphotericin B and 5-fluorocytosine were
switched to liposomal am photericin B (Ambisome®) be­
cause of side-effects of the prim ary drugs. 1 patient did
not receive any antifungal treatm ent, because fungal in­
fection was not clinically evident.
Cough and shortness of breath were common respira­ Table 4. Sensitivity o f bronchoscopy, CT scans, serology and
tory symptoms. 6 patients developed sanguineous, 5 pu­ blood cultures in the diagnosis o f aspergillosis

rulent sputum. Focal inspiratory crackles could regularly

Histologically Total
be heard. 6 patients reported a history o f pre-existing lung proven aspergillosis
disease (chronic obstructive lung disease, n = 2; tuberculo­ (n = 15) (n = 33)
sis, n = 3; fungal pneumonia, n = 1).
Bronchoscopy 6/12 21/28
BAL 4/12 14/28
Microbiological Findings
BS 6/12 21/28
The microbiological findings in bronchoscopic speci­ Thorax CT 7/9 16/19
mens are listed in table 3. Aspergillus spp. were identified Serology’ 1/13 3/33
in 21 out of 28 BAL fluids and/or BS. In patients with Blood culture 0/22 0/61
histologically proven invasive fungal disease, 6 o f 12
aspergilloses were diagnosed by bronchoscopy. The sensi­
tivity of BS was higher than BAL in detecting Aspergillus
infections (table 4).

Fig. 1. Pulmonary aspergillosis (62-year-old male with acute my­
elogenous leukemia). Round inflam mation during the period of
severe neutropenia.
In retrospective analysis, Aspergillus spp. were the only
organisms cultured in 16 episodes. In 17 episodes, asper­
gillosis was mixed with Candida (n = 5), Pneumocystis
carinii (n = 1), cytomegalovirus (n = 2) and/or bacteria as
proven by autopsies, positive blood cultures and/or isola­
tion o f the organisms from bronchoscopic specimens.
Positive serological findings with a significant rise (> 2
titre steps) and/or pathologically elevated titres (> 1:40)
o f Aspergillus IgM antibodies were found in 3 patients.
Yet, only 1 patient showed an appropriate antibody
response during the 1st week o f fungal pneumonia. None
o f the patients had positive blood cultures for Aspergillus
(0/61). 303 surveillance cultures were analysed. With the
exception of 4 patients showing positive sputum cultures,
all cultures of urine, faeces, oropharynx and anal swabs
were negative for Aspergillus.
Radiographic Features
All patients had developed new pulmonary infiltrates
on X-ray. On average, infiltrates were docum ented 7
(range 0-40) days after the onset of fever. Patients with
neutropenia developed radiographic abnormalities signif­
icantly later than patients without neutropenia [9 (0-40)
vs. 2 (1-13) days; p < 0.05]. 29 patients had bilateral dis­
ease. Radiographic abnormalities included round inflam­
344 von Eiff/Roos/Schulten/Hesse/Zuhlsdorf/
van de Loo
mation (n = 18; fig. 1), diffuse large bilateral infiltrates
(n = 15) and cavitation (n = 3). The first manifestation
were usually round-shaped lesions with irregular margins,
which slowly increased in size and sometimes in number.
Intracavitary fungus balls were never detected during the
phase of severe neutropenia and developed in 3 episodes
after bone marrow recovery'. 16 patients had pleural effu­
sions.
High-resolution CT scans of the lungs were done for 19
patients. 12/19 cases had consolidation o f all lobes with
preference for the right lung. Typical CT signs of invasive
pulmonary aspergillosis were found in 16 episodes. Multi­
ple small nodules were equally distributed among all lobes
and were smaller than 1 cm in diam eter in 6, 1-2 cm in
diam eter in 11 patients and/or > 2 cm in 9 cases. The CT
halo sign, a zone of lower attenuation surrounding a pul­
monary mass, was present in 7 patients with early CT
scans obtained during bone marrow aplasia (fig. 2). An air
crescent formation during bone marrow recovery was
documented in 4 of these patients. The CT halo sign pre­
ceded cavitation or air crescent form ation by 7-20 days.
In addition, CT scans showed angiotropic lesions (n = 7),
pulm onary infarction (n = 5), and atelectasis (n = 3). CT
established the presence o f pulm onary infection before
plain films were able to detect infiltrates in 3 patients.
Clinical Outcome
19 (48%) patients died during hospitalization. Patients
succumbed to septicemia (n = 8), respiratory failure (n =
5), pulm onary (n = 5) and cerebral (n = 1) bleeding. Dis­
seminated aspergillosis with spread o f the infection to
other visceral organs was proven by autopsy in 8/13 (62%)
cases. The heart (n = 6) and the brain (n =4) were the most
common extrapulmonary organs involved. Aspergillus ab­
scesses and/or haemorrhagic infarctions were also noted
in the kidneys (n = 3), gastrointestinal tract (n = 3), liver
and spleen (n = 2), thyroid and prostate (n = 1).
Antifungal treatment and its timing influenced the
mortality as follows. The only aspergillosis without anti­
fungal treatm ent was fatal. 9 o f 22 (41%) patients died
who were treated with i.v. antifungal drugs in the first 10
days after onset of pneumonia. Yet, when i.v. antifungal
therapy was started later, mortality rose to 90% (9/10,
p < 0.01). Patients with advanced pneumonias, needing
mechanical ventilation because o f respiratory' failure had
the worst prognosis (11/13,85%, p < 0.025). The mortality
of patients with bilateral pulmonary infiltrates (17/29;
58%) and with mixed fungal infections (11/17; 64%) were
slightly but not significantly higher than in patients with
unilateral infiltrates or monoinfections, respectively.
Early Diagnosis o f Pulmonary Aspergillosis

The prognosis of our patients with aspergillosis has
improved during the last few years. Patients with fungal
pneum onia treated between 1987 and 1989 had a m ortali­
ty of 67% (10/15). Between 1990 and 1992, the mortality
decreased to 50% (9/18; NS). Between the former and lat­
ter periods, the introduction of i.v. antifungal treatment
after onset o f pneum onia has been shortened from 12 to 7
days (p < 0.05). The duration of pneum onia o f surviving
patients has been shortened from 39 (23-64) to 31 (16-
50) days (NS).
Discussion
Invasive pulmonary aspergillosis has become an in­
creasingly im portant cause of m orbidity and mortality in
immunosuppressed patients. The im m une defect most
clearly associated with invasive aspergillosis is prolonged
neutropenia [21, 22]. At a tim e when institution of high-
dose antifungal therapy may improve survival, invasive
biopsy procedures are often prohibited by the patients’
marked thrombocytopenia. Thus, a num ber o f investiga­
tors have used a variety o f laboratory methods in an
attem pt to make an earlier and more reliable diagnosis of
Fig. 2. Early invasive pulmonary aspergillosis in a 45-year-old
male with Hodgkin’s disease, a Bilateral ill-defined infiltrates, partic­
ularly in the upper and lower zones (standing chest X-ray), b Several
nodular lesions (diam eter > 1.0 cm) with a positive halo sign (arrows)
in the right lung. Ground-glass opacity in the left lung (arrowhead)
(standard CT Scan o f the thorax).
invasive aspergillosis in immunocompromized patients.
However, surveillance cultures as well as antibody or anti­
gen detection often present false-negative results [12, 13].
The low sensitivity and specificity o f serologic tests as well
as o f surveillance cultures was reaffirmed by this study.
However, bronchoscopy and CT scans o f the lungs
established or substantiated the early diagnosis of pulmo­
nary aspergillosis in our patients. 6 of 12 histopathologi-
cally proven aspergilloses were diagnosed by bronchosco­
py. In comparison with BAL, BS had a slightly but not
significantly higher sensitivity. Apart from the positive
cultures of Aspergillus, an additional advantage o f bron­
choscopy was the identification of other organisms.
Mixed infections o f Aspergillus with Candida spp., Pneu­
mocystis carinii, herpes viruses and/or bacteria were doc­
um ented in more than half of the patients with invasive
aspergillosis. Comparable data for the diagnostic yield of
bronchoscopy have been published. Albelda et al. [23]
reported a success rate o f 50%. Bronchial washings and
brushings established the diagnosis o f invasive pulmo­
nary aspergillosis in 8 o f 16 patients. In the study o f Kahn
and Jones [16] BAL enabled the diagnosis o f 7 o f 13
patients with invasive fungal pneumonia. Yet, Saito et al.
[24] reported a lower diagnostic yield of BAL in patients
345
 with acute leukemia. BAL detected none of 9 Aspergillus be im proved from 33 to 50%. At the same time, the dura­
pneumonias. In a prospective study into the diagnostic tion of fungal pneum onia of surviving patients was re­
role o f BAL in immunocompromized patients, we found duced from 39 to 31 days. The influence of early appro­
that the detection of Aspergillus spp. in bronchoscopic priate antifungal therapy on survival has also been pub­
specimens was 100% specific [ 15]. The significance of the lished by others [5, 19,27,28].
isolation o f Aspergillus from the respiratory tract in pa­ In conclusion, both techniques, bronchoscopy obtain­
tients with neutropenia was also affirmed in a 3-year pro­ ing BAL fluid and BS and high-resolution CT scans have a
spective study by Yu et al. [25], Identification o f Aspergil­ high diagnostic yield in detecting aspergillosis and are
lus spp. in respiratory secretions of immunocompromized mutually complementary diagnostic approaches. CT scan
patients predicted aspergillosis accurately, with 17 of 17 is a sensitive tool in the early diagnosis o f pulmonary
patients with positive cultures for Aspergillus showing aspergillosis when assessed together with the clinical set­
invasive pulmonary' disease on subsequent diagnostic ting. The identification of Aspergillus spp. in broncho­
biopsy procedures. Yet, other authors reported that iden­ scopic specimens in immunocomprom ized, particularly
tification of Aspergillus in BAL eventually proved to be severe neutropenic patients, proves aspergillosis. From
pathogenic in only 25% of cases, retrospectively [ 17], the data reported here, we arrive at the following recom­
Chest X-ray findings at the onset of infection were mendations. In immunocompromized patients at a high
non-specific and indistinguishable from other infectious risk for pulm onary aspergillosis, particularly patients w'ith
pneumonias, particularly in our patients with neutrope­ prolonged neutropenia, empirical treatm ent with antibi­
nia. CT played an im portant role in establishing the early otics and antimycotics should be started as soon as infil­
diagnosis of fungal pneum onia in these patients and trates are detected on X-ray. Bronchoscopy with BAL and
guided management. In the appropriate clinical setting, BS and a high-resolution CT scan should be performed as
the presence of a CT halo sign strongly supported the diag­ early as possible to establish the diagnosis. Hopefully, ear­
nosis of invasive pulmonary aspergillosis. CT was more ly diagnosis and therapy will significantly improve surviv­
sensitive and, in particular, more specific than conven­ al in these patients.
tional chest X-rays. CT scan recognized fungal disease in
3 cases, where simultaneous conventional chest films did
not show any abnormalities. All 7 cases with radiographic
halo signs and/or air crescent signs were finally confirmed
histologically as invasive pulmonary' aspergillosis. The
contribution of CT to early diagnosis and management of
invasive pulmonary aspergillosis has also been described
by others [ 18-20,26]. The halo-like lesions were shown to
correspond to a central fungal nodule surrounded by a rim
o f coagulative necrosis [ 18]. In this retrospective analysis,
CT diagnosis had the highest sensitivity in the early diag­
nosis of aspergillosis. However, the specificity of the CT
halo and/or air crescent signs must be determ ined in
future studies. Like Kuhlman et al. [19], we have not yet
found docum entation of any infections in neutropenic
patients other than with Aspergillus dem onstrating these
signs.
The more frequent use of bronchoscopy and CT scans
in our departm ent between 1990 and 1992 compared to
1987-1989 resulted in an earlier appropriate antifungal
therapy and led to greater therapeutic success. The start of
i.v. antifungal treatm ent after the onset of pneum onia was
reduced from 12 to 7 days. Early employment of antifun­
gal treatm ent within the first 10 days after onset of pneu­
monia had a significant impact on survival. The survival
of our patients in the more recent treatm ent period could

346 von Eiff/Roos/Schulten/Hesse/Ziihlsdorf/ Early Diagnosis o f Pulmonary Aspergillosis

van de Loo
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