Gundlach et al. BMC Surgery
(2019) 19:200
https://doi.org/10.1186/s12893-019-0668-4

CASE REPORT

Open Access

Lethal thrombosis of the iliac artery caused
by Aspergillus fumigatus after liver
transplantation: case report and review of
the literature
Jan-Paul Gundlach1* , Rainer Günther2, Helmut Fickenscher3, Marcus Both4, Christoph Röcken5,
Thomas Becker1 and Felix Braun1

Abstract
Background: Aspergillus fumigatus infections frequently occur after solid organ transplantation. Yet, a fungal
thrombosis after liver transplantation is an exceptional finding.
Case presentation: We report on a 44-year-old female with an aspergillosis after liver transplantation for
autoimmune hepatitis. On postoperative day (pod) 7, seizures occurred and imaging diagnostics revealed an
intracranial lesion. Anidulafungin was initiated in suspicion of mycosis and switched to voriconazole on suspicion of
an Aspergillus spp. infection. Progression of the cerebral lesion prompted craniotomy (pod 48) and the aspergillosis
was verified. The patient was discharged with oral voriconazole therapy. Re-admission was necessary with acute-onchronic renal failure after a tacrolimus overdose on pod 130. The patient received a pelvic angiography due to a
temperature difference in the legs. It showed a complete iliac artery thrombosis which was subsecutively surgically
removed. The histopathological examination revealed an Aspergillus fumigatus conglomerate. The patient died on
pod 210 due to systemic aspergillosis.
Conclusion: The acute development of focal neurologic deficits is common in patients with an aspergillosis of the
brain. Nevertheless, arterial thrombosis after Aspergillus fumigatus is less frequent and, to the best of our knowledge,
its occurrence after liver transplantation has not yet been reported so far. Due to its rarity, we added a review of
the literature to this manuscript.
Keywords: Aspergillus fumigatus, Liver transplantation, Arterial thrombosis

Background
Fungal infections frequently occur after solid organ
transplantation (SOT). Aspergillus (A.) species account for a significant proportion of these infections,
especially A. fumigatus, which is a contaminant of the
respiratory tract. A. fumigatus produces airborne conidia that can cause infections in immunosuppressed
patients [1]. Infections can involve the lungs, paranasal sinuses, and orbital bones, appearing as chronic
* Correspondence: jan-paul.gundlach@uksh.de
1
Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric
Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel,
and Christian-Albrecht University (CAU), Arnold-Heller-Str. 3, 24105 Kiel,
Germany
Full list of author information is available at the end of the article

granulomatous disease or disseminated infection characterized by tissue necrosis. Invasive aspergillosis is
characterized by vascular invasion and thrombosis.
Central nervous system (CNS) involvement regularly
occurs through hematogenous spread from pulmonary
infections. At the same time, CNS involvement mostly
affects immunocompromised patients, is often accompanied by generalized infections [2] and usually correlates with poor prognosis [3, 4].
The outcome of infections due to aspergillus species in
SOT recipients has been poor. After liver transplantations (LT), cases of invasive aspergillosis have been reported with disastrous outcome: the overall 1-year
cumulative survival probability was reported as 35% [4];

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Gundlach et al. BMC Surgery

(2019) 19:200

and long-term survival remains rare [3, 5]. The majority
of A. fumigatus infections occur in the first 6 months
after transplantation, when immunosuppression is at its
highest level [4].
A. fumigatus infections are difficult to diagnose due
to the low rate of positive cultures. The galactomannan antigen test from serum samples may allow an
early diagnosis even if cultures remain negative due
to antifungal treatment. The rarity of this pathology
makes its therapeutic treatment very difficult on a
multidisciplinary level. The acute development of
focal neurologic deficit is common in patients with
aspergillosis of the CNS and cerebral imaging diagnostics often reveals fungal inflammation [6]. In our
described case, the diagnosis of cerebral aspergillosis
was supposed after the development of focal seizures
and was verified histologically after surgical removal.
Moreover, arterial thrombosis after A. fumigatus is
less frequent and to the best of our knowledge, its
occurrence after LT has not yet been reported so far.

Case presentation
A 44 years old female Caucasian was diagnosed with
autoimmune hepatitis. Histologically, giant cell hepatitis
was discussed. The disease did not respond to a high
dosage of steroids (100 mg for 5 days with consecutive
reduction) with acute-on-chronic decompensation and
the patient was evaluated and listed for LT. The Model
of End Stage Liver Disease score (Lab-MELD) was 33
and the Child-Pugh score was C. Liver transplantation
was performed 5 weeks after first admission in January
2015 with a full-size graft of 1200 g. The female donor
was 72 years old. The cytomegalovirus status was D+/Rand the cold ischemia time lasted 10 h 8 min. The donor
received 11 red blood cell concentrates, five platelet concentrates, and 18 fresh frozen plasma doses. At the time
of LT, microbiological smears showed negative results.
Reoperations with lavage were needed after initial liver
packing. Already on pod 6, cultures from tracheal and
bronchial samples yielded growth of Aspergillus spp.,
and Aspergillus galactomannan antigenemia was demonstrated from pod 0 to 39. During the concomitant postoperative time, the patient suffered from an aspergillus
infection which was primarily suspected after cranial imaging and subsequently detected following the craniotomy due to the abscess removal.
Initial immunosuppression consisted of a steroid induction dosage of 500 mg prednisolone administered
perioperatively, a basiliximab induction 20 mg i.v. on
pod 0 and 4, followed by a low dose tacrolimus and a
prednisolone taper schedule (starting dosage of 20 mg).
The tacrolimus dosage was achieved to a trough level in
the range of 4–6 ng/ml (Fig. 1).

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The standard antibiotic treatment was escalated based
on the evidence of pneumonia within computed tomography (CT) diagnostics with piperacillin, tazobactam and
meropenem, and was switched to daptomycin after
vancomycin-resistant enterococci (VRE) had been isolated repeatedly (Fig. 1). Antifungal therapy was not applied as a standard treatment. An intermittent
haemodialysis was started on pod 5 due to acute renal
failure after LT and continued for 3 weeks, until spontaneous diuresis returned.
Focal seizures occurred on pod 9. Subsequent cranial
diagnostics demonstrated an expansion of the lesion to
the frontal lobe. Further differentiation in cranial
magnetic-resonance imaging (cMRI) revealed multiple
cerebral lesions (Fig. 2). A calculated therapy was started
with anidulafungin on suspicion of an invasive fungal infection. Repeated cMRI scans were performed (Fig. 1).
Following, alongside increasing infectious parameters,
progressive unilateral symptoms and somnolence developed. Nevertheless, repeated MRI showed unaltered
findings. The symptoms were classified as septic encephalopathy. The antimicrobial therapy was escalated again,
and the aforementioned antifungal therapy was changed
to voriconazole. Immunosuppression was administered
with a continuous hydrocortisone infusion.
With further neurologic exacerbation, the MRI showed
progressive cerebral disease. Hence, craniotomy and abscess removal were executed on pod 48. Microbiological
analyses confirmed invasive fungal infection with A.
fumigatus. Hereupon, neurologic symptoms slowly
improved. Three months posttransplant, the patient was
discharged from hospital. The antimicrobial prophylaxis
was cotrimoxazole, valganciclovir and amphotericin B,
as well as a continued antifungal therapy with
voriconazole.
In the time that followed, the patient returned to hospital for 1 week because of gastroenteritis and cytomegalovirus DNA load (DNemia from pod 74 to 117).
Four months posttransplant, the patient was hospitalized
again due to acute-on-chronic renal failure with exsiccosis and hyperkalemia after a tacrolimus overdose. With
widespread intensive care management, dialysis was
evaded. The cMRI suggested intracerebral abscess progress, thus, the antifungal therapy was switched to
posaconazole.
Five months posttransplant (pod 142), a temperature
difference in the legs were noticed. In the following CT
angiography (Fig. 3), an occlusion of the left common
iliac artery (CIA) and of the left internal iliac artery was
detected. After the subsequent operative thrombectomy
on the following day, histopathology proved the presence
of A. fumigatus in the thrombus (Fig. 4). Additionally,
after notice of visual impairment, an invasive fungal infection of the vitreous body was diagnosed and a

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Fig. 1 Postoperative tacrolimus trough. Antimicrobial treatment, operations, imaging procedures and hospitalization are additionally shown. A:
additional laparotomies i.e. removal of abdominal cloths, abdominal lavage, and closure of burst abdomen, respectively. B: craniotomy. C:
thrombectomy. D: vitrectomy

Fig. 2 Cerebral MRI reveals multiple mycotic lesions with peripheral contrast media uptake (a: transverse T1 weighted spin echo sequence,
arrows) and surrounding edema (b: sagittal FLAIR sequence, arrowheads) before craniotomy and subsequent abscess removal

Gundlach et al. BMC Surgery

(2019) 19:200

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Fig. 3 Occlusion of the left common and internal iliac artery (arrows) is detected by CT-angiography

vitrectomy was executed. The visual capacity improved
satisfactorily afterwards.
Under hydrocortisone, the serum bilirubin levels increased and rejection was histologically diagnosed (RAI
6) on pod 195. Galactomannan antigenemia was demonstrated again, starting on pod 197. The antifungal therapy was changed to voriconazole and amphotericin B. A
variceal hemorrhage occurred and the patient was

transferred to our intensive care unit. After all therapeutic approaches had been exhausted, the patient was
moved to our palliative care ward and died 7 months
(pod 210) posttransplant.

Discussion and conclusions
Although reports on A. fumigatus associated thrombosis
following kidney transplantation have been reported [7],

Fig. 4 Histomorphological analysis of conglomerate after thrombectomy. Hematoxylin and eosin (H&E) stained section, as well as PAS staining
showed mycotic inflammation, respectively (both × 40). Fungus demonstration by Grocott staining (× 400). Note: Arrowheads were used to
indicate relevant areas of mycelium. Subsequent DNA analysis verified A. fumigatus

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fungal thrombosis following orthotopic liver transplantation (LT) is unique to the best of our knowledge. We
found one case of portosplenomesenteric thrombosis
following LT after pneumonic superinfection with A.
fumigatus, but, without evidence for fungal thrombosis
[8]. In addition, intracerebral thrombotic complications
following A. fumigatus infections in pediatric LT have
been reported [9].
Immune deficiency supports Aspergillus fumigatus
infections and thrombosis

Arterial thrombosis due to A. fumigatus infection is an
exceptional complication of invasive aspergillosis in immunocompromised patients. Aspergillus is a ubiquitous
fungus in the air [1] and consequently patient’s infection
usually occurs via the respiratory system as a silent carrier leading to pneumonia [10]. In our case, no other
events of systemic aspergillosis were recorded in the
hospital at that time and the patient was healthy prior to
LT. Subsequently, an invasive fungal spread from the patient’s respiratory tract through the bloodstream is considered to be the likely source of infection. Apart from
postoperative intensive care medicine and immunosuppression, no other known risk factors for invasive aspergillosis - such as chronic pulmonary diseases - were
present [11]. In detail, several risk factors for thrombosis
due to A. fumigatus infections have been identified: The
major predisposing factors include prolonged neutropenia, chronic administration of corticosteroids [12, 13],
as well as the insertion of prosthetic devices [14, 15] and
tissue damage due to prior infection or trauma [10]. In
immunocompromised patients, the immune system fails
to eliminate A. fumigatus’ conidia which results in hyphae multiplication and dissemination [16].
Antifungal answer: platelets cure but also clog

The human antifungal protection system consists of different cellular compounds, making itboth a blessing and
a curse: platelets participate by inhibiting the invasionsupporting germination and hyphal elongation [17], and
become activated [18]. The binding to hyphae is an important step in the immune defense against aspergillus
since platelets store antimicrobial peptides and serotonin
which have antifungal effects themselves. Nevertheless,
platelets are unable to internalize conidia but adhere and
cover the fungus [17]. Hence, the mutual impact with
human platelets results in thrombosis and consequently
tissue infarction.
Limited diagnostic prospects and recent treatment
options

Establishing the diagnosis is difficult due to the lack of
positive blood cultures in most cases, nonspecific clinical
presentation, varying clinical course and lack of

Page 5 of 6

definitive imaging characteristics. Furthermore, no optimal strategy exists concerning the timing of surgically
intervention or the duration of conservative treatment.
The serum galactomannan antigen test allowed the early
detection of aspergillosis; however, false-positive results
may hinder its benefit [4]. Elevated galactomannan antigen levels were detectable again only in the very terminal phase.
From 2005, some antifungal agents such as itraconazole
and deoxycholate amphotericin B were no longer considered first-choice drugs for invasive aspergillosis: Therapy
is hindered by CNS aspergillosis in immunocompromised
patients, which has shown excellent response to voriconazole so far. The use of voriconazole was significantly associated with a higher probability of survival (p < 0.001) in a
review including 116 patients suffering from invasive aspergillosis after LT [4]. The overall survival has improved
in the last decade since combined therapies were proven
to be beneficial [4]: similarly, combination regimens with
voriconazole were beneficial for survival (p < 0.001) [4]
and complementary effects were shown for a combination
of voriconazole and caspofungin being independently associated with reduced mortality in patients with A. fumigatus infections [19].
In LT, caspofungin is associated with a significantly
higher risk of adverse events, especially acute renal
failure (p = 0.001), even though it does not carry an apparent increase in the risk of death or acute cellular rejection in LT [20]. Thus, voriconazole is the preferred
antifungal therapy in SOT, regardless of possible influence in the tacrolimus metabolism in human liver
microsomes [21]. Nevertheless, drug interactions of antifungal therapy and immunosuppression must always be
considered. Our switch of antifungal therapy to posaconazole should be critically reviewed. For breakthrough
infections, liposomal amphotericin B or echinocandin
should have been preferred [22]. Furthermore, echinocandins are proposed for prophylaxis of invasive fungal
infections in high-risk patients because of their coverage
of Candida, Aspergillus and Pneumocystis pneumonia,
their low nephrotoxicity and hepatotoxicity, rare drug–
drug interactions and low risk of drug resistance [23].
Future investigations are needed to determine the role
of combined approaches for invasive aspergillosis in LT.
In conclusion, cerebral aspergillosis accompanied by
invasive fungal arterial thrombosis represents a critical
problem for the liver transplant recipient, with a highly
lethal course. Its diagnosis and therapy need to be quick
and precise.
Abbreviations
cMRI: cranial magnetic-resonance imaging; CNS: central nervous system;
LT: liver transplantation; pod: postoperative day; MELD: Model of End Stage
Liver Disease score; RAI: rejection activity index; SOT: solid organ
transplantation

Gundlach et al. BMC Surgery

(2019) 19:200

Acknowledgements
We acknowledge financial support by Land Schleswig- Holstein within the
funding program Open Access Publikationsfonds to cover the costs of
publication.
Ethics approval and consent to participate
The patient has signed an informed consent. This study was approved by
the local institutional review board of the Medical Faculty of the ChristianAlbrechts-University of Kiel (D 400/19).
Consent for publication
A written Consent for Publication was obtained from the patient for the
publication of all potentially identifiable clinical data and accompanying
images. A copy of this consent form is available for review by the editor of
this journal.
Authors’ contributions
JPG wrote the manuscript. RG and HF evaluated the data. MB and CR
prepared the figures. TB and FB supported infrastructure and organizational
issues. All authors read and approved the final manuscript.
Funding
No funding was received for this study.
Availability of data and materials
The clinical datasets supporting the conclusions of this study were derived
from the patient files (paper and electronic form). Therefore, restrictions to
availability apply due to data protection regulations. Anonymized data are,
however, available from the corresponding author on reasonable request
and with permission of the University Hospital Schleswig-Holstein and the
local review board.

Page 6 of 6

7.

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10.

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14.

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18.
Competing interests
The authors declare that they have no competing interests.

19.

Author details
1
Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric
Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel,
and Christian-Albrecht University (CAU), Arnold-Heller-Str. 3, 24105 Kiel,
Germany. 2Department of Internal Medicine I, UKSH and CAU, Campus Kiel,
Kiel, Germany. 3Department of Infection Medicine, UKSH and CAU, Campus
Kiel, Kiel, Germany. 4Department of Radiology and Neuroradiology, UKSH and
CAU, Campus Kiel, Kiel, Germany. 5Department of Pathology, UKSH and CAU,
Campus Kiel, Kiel, Germany.

20.

Received: 28 August 2019 Accepted: 17 December 2019

21.

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