Open Journal of Pathology, 2013, 3, 166-169
Published Online October 2013 (http://www.scirp.org/journal/ojpathology)
http://dx.doi.org/10.4236/ojpathology.2013.34030
A Report of 2 Cases of Disseminated Invasive Aspergillosis
with Myocarditis in Immunocompromised Patients
Tetsuhiro Yoshino1,2, Hiroko Nishida1,3*, Takashi Takita1, Masanori Nemoto1, Michihiro Sakauchi1,
Mami Hatano4, Kazuyuki Koyama5, Masao Hori5, Katsuyuki Obara1
1Department of Internal Medicine, Mito Red Cross Hospital, Ibaraki, Japan; 2Center for Kampo Medicine, Keio University School of
Medicine, Tokyo, Japan; 3Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 4Department of
Pathology, Keio University, School of Medicine, Tokyo, Japan; 5Department of Laboratory Medicine, Mito Red Cross Hospital,
Ibaraki, Japan.
Received August 7th, 2013; revised September 1st, 2013; accepted September 8th, 2013
Copyright © 2013 Tetsuhiro Yoshino et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Invasive aspergillosis is a life-threatening opportunistic infection that occurs most often in immunocompromised pa-
tients, especially those with either hematological malignancies treated with chemotherapy or in organ transplant recipi-
ents. Here, we report 2 cases of disseminated invasive aspergillosis with myocarditis proven pathologically by autopsy.
These 2 cases occurred in immunocompromised patients: the first patient received chemotherapy for acute myeloid
leukemia with myelodysplasia-related changes (AML-MRC); the second patient received methotrexate therapy for
rheumatoid arthritis (RA). Invasive aspergillosis with myocarditis has high morbidity and mortality rates, therefore it is
necessary to make prompt diagnosis and to start intensive treatments quickly.
Keywords: Invasive Aspergillosis; Myocarditis; Acute Myeloid Leukemia; Rheumatoid Arthritis
1. Introduction
Aspergillus species have the ability to cause aggressive
invasive infections in a variety of major organs, includ-
ing the lungs, heart, central nervous system, and gastro-
intestinal tract. These organisms most commonly affect a
variety of immunocom promised patients with hemato-
logical malignancies, especially those who had acute
leukemia under receiving chemotherapy, or organ-trans-
plant patients [1]. Here, we present 2 cases of dissemi-
nated invasive aspergillosis with myocarditis in immuno-
com promised patients who received either chemother-
apy for acute myeloid leukemia (AML) or immunosup-
pressive therapy for rheumatoid arthritis (RA).
2. Case Report 1
A 76-year-old man presented with asymptomatic anemia
in August 2009. The laboratory findings at the initial pre-
sentation were as follows: white blood cell (WBC) count,
2.31 × 103/mm−3 (23% neutrophils, 54% lymphocytes,
10% monocytes, 11% basophils, and 2% eosinophils);
hemoglobin (Hgb) level, 9.1 g/dL; platelet (Plt) count,
11.2 × 104/mm−3. Bone marrow aspiration showed a nor-
mocellular bone marrow consisting of less than 5% mye-
loblasts, accompanied by dysplasia of erythroblasts and
megakaryocytes. Cytogenetic analysis revealed abnor-
malities with 46XY, del(7) (q31q34) in 5 of 20 cells. The
patient was diagnosed with myelodysplastic syndrome
with refractory cytopenia with multilineage dysplasia
(MDS; RCMD). During his clinical course, anemia and
thrombocytopenia had gradually progressed. In August
2011, leukocytosis with the presence of 49.5% immature
monocytes was indicated. Bone marrow aspiration showed
widespread infiltration of CD13+/CD33+/HLA-DR+ im-
mature monocytes which was weakly stained with both
peroxidase and non-specific esterase. Cytogenetic ab-
normalities, including 46XY, del(7) (q31q34) (in 20 of
20 cells), +8, +15 (in 5 of 20 cells), were also observed.
Based on these results, the diagnosis of acute myeloid
leukemia with myelodysplasia-related changes (AML-
MRC) was made. Immediately, low-dose cytarabine che-
motherapy (Ara-C: 20 mg·m−2/day, 14 days) was initi-
ated. However, shortly after initiating Ara-C, the patient
developed high fever which was considered to be due to
either novel infections or adverse effects of Ara-C.
*Corresponding author.

A Report of 2 Cases of Disseminated Invasive Aspergillosis with Myocarditis in Immunocompromised Patients 167
Anti-fungal therapy with liposomal amphotericin B
(AMPH-B), as well as anti-micobacterial therapy was
initiated. However, the patient developed severe neutro-
penia with a WBC count of 0.2 × 103/mm−3 and he went
into shock. An electrocardiogram (EKG) showed both an
elevated ST-T segment in the broad leads and decreased
wall motion, with a low echo region at the apex. The
patient’s clinical course strongly indicated a diagnosis of
fungal myocarditis, therefore the therapy with methyl-
predonisoline (m-PSL; 0.5 mg/kg /day, 3 days) was initi-
ated. Micafungin (MCFG) was also initiated in addition
to liposomal AMPH-B, but no response was obtained and
the patient died. The autopsy findings showed dissemi-
nated invasive aspergillosis involving the lungs, heart,
liver and gastrointestinal tracts (Figures 1(a)-(f)). Leu-
kemia cells were not detected in the extremely hypocel-
lular bone marrow, indicating that leukemia progression
had been denied.
3. Case Report 2
An 81-year-old woman was admitted to our hospital in
October 2011 because of a worsening cough, sore throat,
hemorrhagic stomatitis and melena. Progressive pancy-
topenia; WBC count, 0.23 × 103/mm−3 with 20% granu-
locytes and 80% lymphocytes was also present. She had
been diagnosed with Rhematoid artiritis (RA) at another
clinic at age 76 and had started undergoing hemodialysis
Figure 1. Autopsy results for Case 1, with evidence of inva-
sive fungal infection (hyphae of Aspergillus). (a) Macro-
scopic image of the right upper lobe of the lung showing
cavity lesions with hemorrhagic necrosis (arrow); (b) Dif-
fuse hemorrhagic necrosis was observed in the lung lesion
(hematoxylin and eosin [HE] stain; original magnification,
×100); (c) Grocott stain for Y-angle branching hyphae de-
monstrating massive lung tissue invasion (original magnifi-
cation, ×400); (d) Macroscopic image of the heart, showing
hemorrhagic necrosis in the left ventricle (arrow); (e) In-
flammatory infiltration in the necrotic myocardium (HE
stain; original magnification, ×100); (f) Grocott staining for
the presence of fungi in the myocardium (Grocott stain;
original magnification, ×400).
for chronic renal failure in May 2011. Ten days before
her admission, a single dose of methotrexate (MTX; 2
mg) was administered to control the disease activity of
RA. On her admission, she had high fever and Esche-
richia coli was detected in the blood culture, therefore
anti-micobacterial therapy was immediately initiated. She
was also treated with granulocyte-colony stimulating
factor (G-CSF: 250 µg/day) intraveneously. During her
hospitalization, the pancytopenia gradually improved.
However, the patient suddenly lost her consciousness and
went into shock. Chest imaging did not show any ab-
normal signs. Computed tomography scan of the head
revealed that she had multiple cerebral infarctions. Since
Candida tropicalis and Bacteroides fragilis were simul-
taneously detected in the blood culture, the therapy with
MCFG and metronidazole was started. However, despite
these supportive treatments, her respiratory symptoms
worsened and she died. An EKG showed no definite
change. The autopsy findings showed disseminated inva-
sive aspergillosis affecting the lungs, heart, spleen, and
kidneys (Figures 2(a)-(f)). The bone marrow showed
almost normal cellularity. Although the cause of the cere-
bral infarctions could have been embolization caused by
Aspergillus species, the patient’s family did not consent
to opening her skull for autopsy.
4. Discussion
Invasive aspergillosis is a serious opportunistic infection
that occurs in a variety of immunocompromised patients,
Figure 2. Autopsy results for Case 2, with evidence of inva-
sive fungal infection (hyphae of Aspergillus); (a) Macro-
scopic image of the left upper lobe of the lung, showing a
10-mm nodule (arrow); (b) Fungal hyphae are seen prolif-
erating radially from the lung wall (HE staining; original
magnification, ×100); (c) Grocott staining for Y-angle bran-
ching fungal hyphae in the lung tissue (original magnifica-
tion; ×400); (d) Macroscopic image of the heart; (e) Abscess
lesion observed in the myocardium (HE stain; original
magnification, ×100); (f) Grocott staining for the presence
of fungal hyphae in the myocardium (original magnification,
×400).

A Report of 2 Cases of Disseminated Invasive Aspergillosis with Myocarditis in Immunocompromised Patients 168
such as those receiving chemotherapy for hematological
malignancies or organ-transplant patients and it has high
morbidity and mortality rates. Its incidence has been es-
timated at around 10% - 14%, and the mortality rates
may be as high as 27% - 60% in spite of antifungal ther-
apy [2,3]. In order to reduce mortality rates, to make a
diagnosis quickly and to initiate intensive treatments are
necessary. However, premortem diagnosis of invasive
aspergillosis is difficult, because cultures were unreliable
and to assess to the sites was limited [2,3].
Autopsy results in Japan have shown that the preva-
lence of visceral mycoses markedly increased from 3.7%
in 1993 to a peak of 4.6% in 2009. Aspergillus became
the predominant causative pathogen and the rate of as-
pergillosis exceeded that of candidiasis in 1994; it has
continued to increase conspicuously and was even higher
in 2001 (46.0%) [4,5]. On the other hand, since 2001,
there has been a slight decrease in the frequency of as-
pergillosis because of the development of novel, effec-
tive antifungal agents and advancements in non-invasive
diagnostic tools. In addition, an increasing number of
cases with collagen diseases as the underlying cause of
visceral mycosis and a decreasing number of cases with
leukemia as the underlying disorders were noted. How-
ever, overall, invasive aspergillosis are still one of the
most serious infections not only in patients with malig-
nant diseases but also in those with recieving steroids or
immunosuppressive therapy for a variety of diseases
[4,5].
The lung is the most common primary site of invasive
aspergillosis with secondary hematogenous dissemina-
tion. Once Aspergillus forms abscesses in the lung, it can
invade blood vessels and disseminate to the entire body.
Cases of cardiac invasive fungal infection is difficult to
prove premortem and has an especially high mortality
rate. In the case of Aspergillus endocarditis, the mortality
rate reaches 96% if the patient is treated by medication
alone, and 68% even if surgical resection is performed
[6-9]. It is difficult to make a diagnosis of aspergillus
myocarditis, because it requires histopathological evi-
dence of characteristic fungal hyphae or positive culture
results, yielding aspergillus species from myocardial spe-
cimens. Our patients discussed here showed disseminated
invasive aspergillosis with myocarditis that was proven
by autopsy. In Case 1, hemorrhagic necrosis was shown
in the left ventricle and the presence of fungal hyphae in
the myocardium was demonstrated. In Case 2, Abscess
lesion observed in the myocardium and fungal hyphae in
the myocardium was also detected. Both cases had sev-
eral common risk factors for developing disseminated
invasive aspergillosis. These factors include the underly-
ing disease, long-term immunosuppressive therapies in-
cluding steroids, prolonged neutropenia or neutrophil
dysfunction and the use of broad-spectrum antibiotics
which affect mucosal barriers [2,3]. Leukemia and MDS
have been the major underlying diseases to develop inva-
sive aspergillosis, followed by solid cancers and bacterial
infections and only a few reports have been published in
which invasive aspergillosis with myocarditis was proven
pathologically [4,6-8,10]. In Case 2, pancytopenia due to
severe bone marrow suppression occurred after the pa-
tient received MTX. It was considered to be an adverse
effect of MTX due to renal insufficiency and it may be-
came the risk factor to develop invasive aspergillosis
with myocarditis in Case 2. In most reported cases, it is
difficult to determine what to extent the myocarditis con-
tributed to the patient’ death. The clinical course of as-
pergillus myocarditis is extremely short and results in
fatality, so EKG changes consistent with severe symp-
toms was not necessarily revealed. Williams reported
only 6 cases of 37 cases of secondary aspergillosis in
which the myocardium was involved had electrocardio-
graphic changes consistent with ischemia of myocardial
infarction [11]. In our case, Case 1 showed positive elec-
trocardiographic and echographic changes, correlating
with ischemia. We believe that our cases certainly died
of asperugillus myocarditis and subsequent heart failure,
by its extremely quick clinical course, laboratory and
necropsy findings and the absence of other alternative
etiologocal findings.
5. Conclusion
In conclusion, we reported 2 cases of disseminated inva-
sive aspergillosis with myocarditis, which were all con-
firmed by autopsy. These 2 cases involved immunocom-
promised patients receiving chemotherapy or immuno-
suppressive therapies. Invasive aspergillosis, especially
in cardiac infection including myocarditis, has high mor-
bidity and mortality rates. It is therefore necessary to
provide early diagnosis and intensive treatments, includ-
ing novel antifungal therapies.
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Abbreviations
AML-MRC: acute myeloid leukemia with myelodyspla-
sia-related changes;
RA: rheumatoid arthritis;
WBC: white blood cell;
Hgb: hemoglobin;
Plt: platelet;
MDS-RCMD: myelodysplastic syndrome with refractory
cytopenia with multilineage dysplasia;
Ara-C: cytarabine arabinoside;
AMPH-B: amphotericin B;
EKG: electrocardiogram;
MCFG: micafungin;
MTX: methotrexate;
G-CSF: granulocyte-colony stimulating factor.