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CASE REPORT
Fever and Peripheral Emboli in an Immunocompetent Host:
A Case of Aspergillus Endocarditis
Derek Yung 1, Sadiya Kukaswadia 1, Asma Ali 1, Shariq Haider 2 and Omid Salehian 3
1
Department of Medicine. 2Division of Infectious Diseases. 3Division of Cardiology, McMaster University,
Hamilton, Ontario, Canada.
Abstract: Despite diagnostic and therapeutic advances in medical, surgical, and critical care, the mortality rate for Aspergillus
endocarditis remains dismal (approaching 100%). We report a case of a 49 year old immunocompetent woman with recent
aortic valve prosthesis who presents with fever, chills, sweats, left facial droop, left arm weakness, petechial rash and cyanotic
toes. Initial trans-esophageal echo was normal but a repeat study revealed a 9 × 5 mm vegetation abutting the aortic prosthesis. Microbiological correlation could not be documented despite the presence of persistent fever through serial blood
cultures, and the diagnosis of Aspergillus fumigatus endocarditis was ultimately made on embolectomy specimen when she
developed an ischemic right leg. Aggressive medical treatment was initiated with intravenous voraconazole, liposomal
amphotericin-B and heparin. The timing of surgical intervention was contemplated, but was precluded by multiple
comorbidities. She succumbed to her illness after developing cerebral herniation following intraparenchymal
hemorrhage.
The effectiveness of combined medical intervention and surgical valve replacement for Aspergillus endocarditis is
therefore contingent on high diagnostic suspicion and early echocardiographic detection in a high risk individual with
features of culture-negative endocarditis.
Introduction
Aspergillus is a common ubiquitous mold and the broad spectrum of invasive disease attributed to these
fungi has traditionally been observed in the immunosuppressed population. Endocarditis is a rare and
serious disease manifestation of Aspergillus infection and the combination of poor recognition and lack
of effective therapies has led to dismal prognosis. In the immunocompetent host, factors that have been
implicated include prolonged broad-spectrum antibiotic use, indwelling central venous catheters, intravenous drug use, and previous valvular disease or surgery. The latter has become more relevant with
increasing use of intracardiac devices and prostheses and may account for at least 50% of documented
Aspergillus endocarditis cases. A case of endocarditis secondary to Aspergillus fumigatus post cardiac
valve replacement surgery is described, and challenging issues pertaining to diagnosis and management
will be discussed.
Case Presentation
A 49-year-old immunocompetent woman was admitted to hospital with a two day history of progressive
fever, chills, sweats, left facial droop, left arm weakness, petechial rash and cyanotic toes. Two months
prior, she had a redo aortic valve replacement with a #23 Cardbomedic™ mechanical aortic valve for
progressive stenosis of previous mechanical prosthesis which was implanted for rheumatic stenosis.
She had a history of rheumatic fever as a child, requiring aortic and mitral mechanical valve replacements
at age 18 and 39 respectively. Other medical history was significant for hypertension, hyperlipidemia,
atrial fibrillation requiring atrioventricular nodal ablation and pacemaker implantation in 1999, remote
left arm deep venous thrombosis (DVT) and breast cancer in remission treated successfully with surgery
and radiation therapy. Her medications included aspirin, warfarin, and ramipril. There was no history
of prolonged antibiotic or intravenous drug use.
On initial examination she was febrile at 102 oF with otherwise stable vital signs and normal level
of consciousness. Neurologically a left facial droop with forehead sparing was present. Auscultation
revealed crisp and normal metallic opening and closure clicks of the aortic prosthesis, and a previously
Correspondence: Omid Salehian, McMaster University Medical Centre, 1200 Main Street West, Room 3U8,
Hamilton, ON, L8N 3Z5, Canada. Tel: (905)521-2100; Ext: 73822; Fax: (905)521-5053; Email: [email protected]
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Clinical Medicine: Cardiology 2008:2 229–234
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Yung et al
documented grade 2/6 murmur was heard at the
left sternal border. No extra heart sounds were
audible and no signs of heart failure were present.
Inspection of the extremities revealed a petechial
rash over the medial aspect of the left thigh, and
purplish cyanotic discoloration of the left big toe
and right fifth toe. No other embolic or immunologic phenomena of endocarditis were detected.
Initial blood work was unremarkable with a
hemoglobin of 11.7 g/dL, platelet count
of 400,000 /uL, white blood cell count of 8,500/uL,
and normal renal function, liver enzymes and cardiac markers. Immunologic work up including a
screening panel for vasculitic and connective tissue
processes (ie. endonuclear antibodies and antineutrophil cytoplasmic antibodies) was negative
and immunocompetency was verified through
normal CD 4 and CD 8 counts. The international
normalized ratio (4.8), erythrocyte sedimentation
rate (67 mm/h, normal ⬍30 mm/h), and CRP
(33.5 mg/L, normal ⬍3 mg/L) were elevated.
Multiple blood cultures were negative. Computed
tomography (CT) of the head showed (Fig. 1) two
localized areas of acute infarction in the right
insular cortex and right frontal lobe, the latter
with a focal region of intraparenchymal hemorrhage. This clinical presentation was highly
suspicious of peripheral embolic phenomena to
the brain. However, initial trans-esophageal echocardiography did not reveal a cardiac source of
embolization.
Without a clear diagnosis no specific therapy
was initiated. The presence of mechanical valvular
prosthesis in the setting of intracranial hemorrhage
required judicious anticoagulation with intravenous
heparin, and discontinuation of aspirin and warfarin
therapy. The intermittent fevers continued in the
presence of new onset photosensitivitiy and
Figure 1. Brain computed tomography (without contrast) showing the right frontal lobe infarct (arrow).
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Fever and peripheral emboli in an immunocompetent host
bilateral conjunctival injection, stable neurologic
symptoms, and negative serial blood cultures. One
week after admission, acute pulseless right leg
ischemia ensued necessitating urgent embolectomy. The embolectomy specimen ultimately grew
Aspergillus fumigatus, and repeat transesophageal
echocardiogram (next day) revealed a 9 × 5 mm
vegetation abutting the posterior aspect of the
bileaflet aortic prosthesis associated with increased
valve gradients (Fig. 2). Aggressive medical
treatment was initiated with intravenous
voraconazole 330 mg twice a day, and intravenous
liposomal amphotericin-B 400 mg daily. The
timing of surgical intervention was contemplated,
but was precluded by multiple comorbidities
mainly the intracranial emboli associated with
generalized seizures, and the risk of intracranial
hemorrhage with full anticoagulation required for
the bypass run. The patient had also developed
Escherichia coli urinary tract infection, and
Figure 2. A) Transesophageal echocardiogram view in midesophageal window showing a short-axis view of the aortic mechanical prosthesis.
There is a mobile echodensity (arrow) seen in the posterior aspect of the prosthesis. B) Long-axis view of the aortic mechanical prosthesis
showing the same echodensity (arrow).
Clinical Medicine: Cardiology 2008:2
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Yung et al
unremitting right-sided flank pain. Radiological correlation via repeat CT scans documented a large left
parietal brain infarct (Fig. 3), and embolic phenomena
to the right kidney and spleen. Given the brain CT
findings and the patient’s clinical condition intravenous heparin was discontinued and anticoagulation
was reversed using vitamin K and fresh frozen
plasma. Intravenous phenytoin was initiated for the
seizures and the patient was intubated in order to
implement hyperventilation to treat the increased
intracranial pressure. Her level of consciousness
continued to deteriorate and ultimately she succumbed to her illness after developing cerebral herniation. Autopsy results confirmed multifocal
microencephalitic microabscesses in the brain consistent with aspergillus meningitis and aspergillomas.
Discussion
Fungal endocarditis accounts for roughly 1.3%–6%
of all cases of endocaridits[1, 2], and complicates
approximately 0.1% of all valve prostheses[2, 3].
Aspergillus endocarditis is second only to Candida
as a cause of fungal endocarditis and accounts for
approximately one in every four cases of fungal
endocarditis. Although numerous Aspergillus
species have been historically isolated, Aspergillus
fumigatus accounts for the vast majority (60%–90%)
of cases reported followed by Aspergillus terreus
(5%–20%)[2]. Men are affected more commonly
than women[4], at a mean age of 40[2].
As depicted by our patient, one of the greatest
challenges and predictors of survival is early recognition. An approach to recognition and management of
Aspergillus endocarditis is shown in Table 1. The
clinical presentation of Aspergillus endocarditis tends
to be non-specific and limited to fever, a new or
dynamic heart murmur and major peripheral
emboli[1, 2, 4, 5]. The latter is the initial presenting
feature in 69%–83% of case, resulting in neurologic
impairment in up to 30% of cases[6]. Less common
presentations include congestive heart failure or sepsis.
The prolonged mean time to diagnosis is estimated at
41 days from symptom onset[1]. With the advent
Figure 3. Brain computed tomography (with contrast) showing effacement of all cisterns and There is a new extensive infarct in the territory
of the left middle cerebral artery involving frontal parietal occipital and posterior temporal areas.
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Fever and peripheral emboli in an immunocompetent host
Table 1. Approach to patient with possible Aspergillus endocarditis.
1. High index of suspicion is necessary
2. Routine blood cultures are almost always negative
3. Transesophageal echocardiography (should be repeated if initially negative and there is a change in
patient’s clinical status)
4. Neuroimaging (due to high degree of systemic embolization)
5. Initiation of aggressive antifungal regimen (Voraconazole/Amphotericine B)
6. Involvement of cardiovascular surgery early in management of patient
7. Role for other diagnostic tests (polymerase chain reaction, galactomannan antigen detection) not clear at
this time
of improved echocardiographic imaging, its use
in the presence of clinical suspicion in a high risk
individual is quintessential. Although adherence
by Aspergillus to mechanical prostheses has not
been objectively evaluated in experimental studies,
the role of protease mediated angio-invasiveness
and gliotoxin mediated protection from phagocytic activity are well accepted virulence mechanisms which probably play an important role in
prosthetic valve infections[7, 8]. Aspergillus
vegetations on the valves tend to be large and
readily detectable by echocardiography in 81.4%
of cases, and occasionally myocardial abscess is
detected in 5.9% of cases[2]. However in a patient
with prosthetic valve, the sensitivity decreases to
76.5% and 61.1% with transthoracic and transesophageal echocardiography respectively. This
is secondary to the confounding effect of high
reflectivity from mechanical valves, and difficulty
differentiating from mural thrombi due to
anatomical distortion[9].
A definitive confirmation of diagnosis is dependent on microscopic, histopathological and microbiological documentation. Yet unlike Candida
endocarditis, blood cultures as entailed in Duke’s
criteria are almost always negative (in 70%–89%
of cases) and isolation in embolic material or
affected tissues is almost always necessary[2, 5, 10].
In our patient, all 11 blood cultures performed were
negative and isolation of Aspergillus fumigatus was
identified only upon urgent embolectomy after suffering peripheral embolization, an unfortunate but
common scenario. The use of novel techniques
including galactomannan antigen detection (an
Aspergillus cell wall constituent), polymerase chain
reaction, or nucleic acid sequence amplification,
has shown a lack of sensitivity and inconsistent
results, has not been sufficiently validated and
requires further characterization[11–13]. Once a
diagnosis is made initiating key management decisions must be made in a timely fashion.
Clinical Medicine: Cardiology 2008:2
Confronting the challenge of implementing
effective medical therapy has been an ongoing
struggle. The mainstay of medical therapy for
Aspergillus endocarditis has been intravenous
Amphotericin B since its introduction in the 1955,
yet the key therapeutic questions of optimal dosage,
duration of therapy and rates of infusion remain
controversial[14]. Nephrotoxicity is the most
common concern associated with this therapy,
although the intercalation of the drug into liposomes has decreased its renal toxicity[15]. Despite
its fungicidal properties, the disappointing results
historically observed in practice have been partly
attributed to poor penetration of fibrin clots and
vegetations, and titration to higher dosages (up to
5 mg/kg for liposomal Amphotericin B) is generally recommended in patients with relatively preserved renal function[16]. Itraconazole an
alternative to Amphotericin B, has been inundated
with problems including multiple drug interactions
and variable bioavailability. In recent years, the
use of Voriconazole has shown promise with a
mortality benefit (hazard ratio 0.59, 0.40 to 0.88
95% CI) at 12 weeks compared to Amphotericin
B therapy shown in a randomized control trial by
Herbrecht and colleagues[17]. In our patient, both
drugs were employed given the refractory state of
her illness. The use of rifampin as a potentiating
agent for Amphotericin B has not been substantiated
by clinical data and independently has no activity
against Aspergilli[18]. Medical therapy however
is almost never sufficient.
Surgery is almost empirically used as an adjunct
to medical therapy, and some may argue that Aspergillus endocarditis is a standalone indication for
valve replacement. The typical surgical protocol
includes debridement of infected tissue, and reconstruction with biologic tissue when possible[3].
The additional magnitude of short and long term
survival benefit from surgery has been long
debated, and the timing of such a major operation
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Yung et al
is often precluded in these critically ill patients.
The post-operative recurrence rate of Aspergillus endocarditis may approach 40%[19], and
combination (medical and surgical) therapy may
not necessarily improve prognosis with mortality rates exceeding 80%[1, 2]. It is therefore
critical to recognize the narrow window of
opportunity for surgical intervention and to
proceed promptly.
The American College of Cardiology and
American Heart Association 2005 recommendations discuss a well accepted two phase therapy
consisting of an induction phase comprised of a
combination of surgical valve replacement and
parenteral antifungal therapy for 6 weeks, followed by a second phase of lifelong suppressive
therapy with an oral azole agent given high relapse
rates[2, 10, 20, 21]. However, the effectiveness of
this approach for Aspergillus endocarditis is contingent on maintaining high diagnostic suspicion
and early echocardiographic detection in a high risk
individual with features of culture-negative
endocarditis.
Aspergillus endocarditis after prosthetic valve
surgery is associated with an ominous prognosis,
and our inability to improve the current dismal
mortality rates has been attributed to a poor implementation of effective medical and surgical interventions early before the viscous cycle of
complications ensues. The burgeoning concept of
percutaneous valve implantation may reduce the
incidence of fungal endocarditis in the long-term
future, but is far from a reality. Meanwhile an
aggressive multidisciplinary approach incorporating
new robust diagnostic, medical and early surgical
therapies is needed.
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