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Previous Article | Next Article 
Journal of Clinical Microbiology, November 1998, p. 3347-3351, Vol. 36, No. 11
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Endocarditis and Aortal Embolization Caused by Aspergillus
terreus in a Patient with Acute Lymphoblastic Leukemia in
Remission: Diagnosis by Peripheral-Blood Culture
G.
Schett,1,2,*
B.
Casati,3
B.
Willinger,4
G.
Weinländer,5
T.
Binder,6
F.
Grabenwöger,7
W.
Sperr,1
K.
Geissler,1 and
U.
Jäger1
Department of Hematology,1
Department of Rheumatology,2
Department of Clinical Pathology,3
Department of Clinical Microbiology,4
Department of Oncology,5
Department of Cardiology,6 and
Department of Radiology,7 General
Hospital Vienna, University Clinic Vienna, Vienna, Austria
Received 13 February 1998/Returned for modification 8 April
1998/Accepted 6 July 1998
 |
ABSTRACT |
Disseminated infection with Aspergillus terreus is a
rare disease that affects only the immunocompromised host. We report a
case of systemic infection with A. terreus resulting in
endocarditis, aortic embolization, and splenic infarction in a patient
with acute lymphoblastic leukemia. Diagnosis through peripheral blood culture, lack of pulmonary involvement, and onset of disease during complete remission from leukemia constitute uncommon features of this
case.
| |
TEXT |
Aspergilli are widespread molds
populating virtually every site of organic debris (9). In
the case of a normal human immune system, Aspergillus
species do not cause systemic disease, which is restricted to the
immunocompromised host (2, 12). More than 200 different
species of Aspergillus are known, but only a few are
consistently pathogenic. A. fumigatus and A. flavus are the most frequently isolated species (2),
whereas systemic infection with A. terreus is a rare
disease, and fewer than a dozen cases have been reported elsewhere
(4, 6, 8, 10, 15, 16). Local infections such as keratitis
and otitis media (11, 14), as well as limited invasive
disease in three patients with endocarditis, have been described
elsewhere (3, 7, 13). Systemic infections occurred only in
severely immunocompromised patients and always included a pulmonary
involvement in these reports, and their outcome was fatal. We report a
case of systemic infection with A. terreus in a patient with
acute lymphoblastic leukemia and describe the uncommon features of this
case.
Case report.
A 60-year-old Caucasian woman was diagnosed with
Philadelphia chromosome-positive (bcr-abl
translocation-positive), acute lymphoblastic leukemia in February
1997. Polychemotherapy according to the German ALL Study Group
protocol (5) was initiated, and complete remission was
achieved after phases I and II of induction chemotherapy (June 1997).
Apart from an episode of Pseudomonas aeruginosa sepsis in
February, the chemotherapy was well tolerated. In October 1997, the
patient was hospitalized due to persistent fever (38.5°C) starting 6 weeks previously. Repeated outpatient examinations did not show any
sign of pulmonary or urinary tract infection, and empirical antibiotic
therapy with amoxicillin, clarithromycin, ciprofloxacin, and
clindamycin did not result in cessation of fever.
Upon admission, the patient was in relatively good general condition
but complained of fatigue, lack of appetite, and fever (as high as
38.5°C). Physical examination revealed arrhythmia due to atrial
fibrillation, mild tachycardia, a faint systolic heart murmur over the
mitral valve, and bilaterally weakened leg pulses. Laboratory
investigation disclosed moderate anemia (hemoglobin, 10.0 g/dl) and
thrombocytopenia (80,000/µl) but normal leukocyte counts
(6,000/µl). Differential blood counting showed 78% granulocytes, 14% lymphocytes, and 8% monocytes. Acute-phase parameters (C-reactive protein, 4.6 mg/dl; blood sedimentation rate, 35/70; fibrinogen, 432 mg/dl) were elevated, and a mild cholestasis (alkaline phosphatase, 339 U/liter; 
-glutamyl transpeptidase, 35 U/liter) was detected. Bone
marrow biopsy did not reveal signs of leukemic infiltration. Repeated
analysis of urine specimens showed no signs of infection.
Multiple blood cultures were performed on days 1, 2, 3, 6, 7, 9, and 11 (after admission), and growth of A. terreus was observed on
days 1 (three positive cultures), 2, 3, 7, and 9 (Fig.
1). Chest X-irradiation was normal, i.e.,
did not show any signs of inflammatory infiltrates. Transesophageal
echocardiography disclosed vegetation (3.7 by 1.2 cm in diameter) on
the posterior part of the mitral valve with protrusions into the left
atrium and infiltrations of the subvalvular and ventricular endocardium
(Fig. 2), causing mild mitral valve
insufficiency. Abdominal computed tomography (CT) revealed a massive
aortic embolization with a thrombus located in the lower abdominal
aorta and left iliac artery, with almost complete occlusion of the
vasal lumen in these segments (Fig. 3).
Despite massive embolization, clinical signs of hypoperfusion or
ischemia of the lower extremities were confined to bilaterally weakened
leg pulses. In addition, embolic infarctions in the spleen and kidneys
were detected by means of CT examination.
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FIG. 1.
Lactophenol blue stain of A. terreus hyphae
from a peripheral blood culture. Magnification, ×100.
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FIG. 2.
Transesophageal echocardiography of valvular vegetations
(veg) caused by A. terreus; protrusion of mitral valve (MV)
fungal vegetations into the left atrium (LA). LV, left ventricle.
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FIG. 3.
CT scan 2 cm above the aortal bifurcation. Arrows,
aorta; white ring, perfused lumen; gray area, central blockage of
perfusion due to a thrombus.
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Drug therapy with amphotericin B (1 mg/kg of body weight) was initiated
8 days after admission, and heart surgery with excision of vegetations
from the valve and subsequent valve reconstruction were performed 1 day
later. Histologic assessment showed fungal endocarditis, with excessive
hyphal spreading and massive destruction (Fig.
4). Cultivation of valvular tissue on
Sabouraud dextrose agar confirmed the growth of A. terreus.
The patient required intensive-care management after heart surgery;
after 3 days, recolonization of the mitral valve with fungal
vegetations was detected by echocardiography. The patient deteriorated
rapidly, showing signs of fungal sepsis, including massive increases in
leukocyte count, acute-phase parameters, and liver enzymes, along with
decreases in erythrocyte and thrombocyte values to counts even lower
than those observed upon her admission. The patient died on day 15 despite intensive-care management. Postmortem examination confirmed
recurrence of fungal endocarditis, as well as fungal aortic
embolization and multiple splenic and renal infarctions.
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FIG. 4.
(A) Periodic acid-Schiff stain of mitral valve tissue
showing complete infiltration with broad hyphae of A. terreus. Magnification, ×40. (B) McManus stain of mitral valve
tissue (blue) showing infiltration of A. terreus hyphae
(violet). Magnification, ×100.
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Mycologic results.
During a period of 11 days, 19 blood
cultures were inoculated. In each case, two bottles, both aerobic and
anaerobic, were filled with 10 ml of blood and incubated at 35.5°C in
a VITAL system (bioMérieux, Marcy l'Etoile, France), a fully
automated instrument for the detection of growing microorganisms.
Readings were taken every 15 min. No positive signal was given by the
detection system at any time. However, all of the bottles were also
checked visually; seven of them showed hyphal growth after 5 days of
culture. A certain amount of each positive blood culture was inoculated onto Sabouraud glucose agar (SAB), and the inoculation was incubated at
35°C. After a few days, the colonies were examined macro- and microscopically. Material obtained from the mitral valve was also cultured on SAB at 35°C.
In total, 7 blood cultures were positive, revealing growth of a mold,
while 12 cultures remained sterile. After subcultivation of the
positive cultures, cinnamon-brown colonies with granular to velvety
textures were observed on SAB. Microscopically, the colonies showed
long slender and smooth conidiophores, as well as columnar conidium
heads with biseriate phialides, which were indicative of the presence
of A. terreus (Fig. 1). In addition, culture of the
mitral valve yielded growth of A. terreus.
Histology.
Mitral valve tissue samples were obtained during
surgery and were fixed in formalin. Paraffin sections (4 µm) were
obtained and stained with periodic acid-Schiff (Fig. 4A), McManus (Fig. 4B), and Grocott (not shown) stains to demonstrate dichotomously branched septate hyphae of A. terreus within the tissue.
Discussion.
Systemic infection with A. terreus is a
rare event, and only nine cases have been described in the literature.
The case described herein shows remarkable differences regarding
diagnostic, clinical, and pathological features compared with the cases
reported previously.
First, primary diagnosis of aspergillosis was achieved by isolation of
the fungi from blood cultures. Isolation of Aspergillus species from peripheral blood cultures is highly uncommon, even in the
case of disseminated disease, and A. terreus has not been isolated from blood cultures of living patients before, while one case
of postmortem isolation from peripheral blood has been reported
elsewhere (9). Even in the case of generalized disease, blood cultures have remained persistently negative (1, 4, 6, 8,
10, 15, 16). Special localizations of A. terreus growth directly exposed to the blood flow, as in the case of the valvular endocardium, may lead to persistent detachment and
embolization of fungi, favoring detection by blood culture.
Second, the lack of pulmonary involvement in the presence of
generalized infection with A. terreus is unique, since all
earlier cases reported to date included severe pulmonary disease. None of the nine chest X rays revealed the presence of aspergilloma or
invasive pulmonary aspergillosis. Furthermore, postmortem macro- and
microscopic assessments of serial lung sections showed no signs of
pulmonary disease. Despite the lack of clinical and pathological signs
of a pulmonary port of entry, infection through the respiratory tract
cannot be ruled out, since the respiratory tract is considered the
usual port of entry for these organisms (16), no venous access device had been in place during the onset of fever, and preceding bacterial sepsis with pneumonia might have caused pulmonary tissue damage, facilitating fungal entry.
Third, the strongest risk factor for disseminated aspergillosis is
prolonged granulocytopenia in the context of immunosuppressive drug
therapies (17). Five of nine cases of generalized A. terreus infections occurred in the complete absence of
granulocytes. In contrast, our patient presented in complete remission
from leukemia, and leukocyte and granulocyte counts were normal at the
onset of infection. Maintenance chemotherapy with oral methotrexate and
purinethole, which was administered during the onset of fever, may have
triggered fungal infection. Alternatively, tissue damage caused by
bacterial infection is known to favor aspergillosis (2), and
the episode of P. aeruginosa sepsis during induction chemotherapy may have entailed colonization with A. terreus.
However, echocardiographic examination, as well as assessment of
Aspergillus antigen and antibodies, was negative at that
time. Despite discontinuation of maintenance chemotherapy and despite
the presence of normal peripheral blood counts, the fever persisted and
disease progressed.
In accordance with the cases of disseminated A. terreus
infection described earlier, the outcome in our patient was also fatal, with a survival of only 15 days after the first positive blood culture.
Although amphothericin B was administered in high doses and in
liposomal form, it did not influence the course of disease. In
addition, heart surgery performed to remove fungal vegetations was not
successful, since fulminant recolonization occurred.
We conclude that A. terreus infection can occur in
nongranulocytopenic patients after chemotherapy and that blood cultures may detect the presence of fungal growth, while lack of pulmonary aspergillosis does not necessarily exclude a systemic infection with
A. terreus.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Internal Medicine III, University of Vienna, Währinger
Gürtel 18-20, A-1180 Vienna, Austria. Phone: 431-40400-4300. Fax:
431-40400-4306. E-mail: GS{at}BCH.UNIVIE.AC.AT.
| |
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Journal of Clinical Microbiology, November 1998, p. 3347-3351, Vol. 36, No. 11
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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