Journal of Infection and Chemotherapy 27 (2021) 1520–1524

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Journal of Infection and Chemotherapy
journal homepage: www.elsevier.com/locate/jic

Case Report

A fatal case of Exophiala dermatitidis meningoencephalitis in an
immunocompetent host: A case report and literature review
Hai-Ying Yu, Ting-Ting Qu, Qing Yang, Jian-Hua Hu, Ji-Fang Sheng *
State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd,
Shangcheng District, Hangzhou, Zhejiang, China- 310003

A R T I C L E I N F O

A B S T R A C T

Keywords:
Exophiala dermatitidis
Central nervous system infection
Antifungal therapy
Immunodeficiency

Background: Central nervous system (CNS) infection due to Exophiala dermatitidis is rare and fatal, and primarily
reported in immunocompromised patients or those with caspase recruitment domain-containing protein 9
deficiency. Herein, we describe a case of an otherwise healthy person (without underlying disease or gene
deficiency) diagnosed with Exophiala dermatitidis meningoencephalitis. The patient achieved clinical remission
under high-dose antifungal therapy in the first 14 months but died after 2 years of the therapy.
Case presentation: A 15-year-old student with headache and fever was admitted to our department. Lumbar
puncture showed increased cerebrospinal fluid (CSF) pressure, moderately high CSF protein levels and cell
counts, and a remarkable decrease in CSF glucose and chloride. Magnetic resonance imaging of the brain
revealed multiple lesions and cerebral pia mater enhancement. CSF culture confirmed E. dermatitidis infection.
We administered 4-week antifungal therapy of amphotericin B, but his CSF culture remained positive. After
receiving the 12-week standard dose of voriconazole (200 mg q12h), the patient’s CSF culture became negative,
but his condition deteriorated with intracranial lesion enlargement. We administered a high-dose voriconazole
therapy (600–800 mg per day) for 12 months, which led to clinical remission. The voriconazole dose was reduced
due to adverse effects including hepatic dysfunction and hypokalemia, and the disease progressed with high
intracranial pressure and epileptic seizures.
Conclusions: CNS infection caused by E. dermatitidis is fatal and the most serious form of fungal infection. Initially,
high-dose and long-term antifungal therapy could be effective. Gene defect and related antifungal immunode­
ficiency may be the most important pathogenic and lethal factor.

1. Introduction
Central nervous system (CNS) infection caused by Exophiala der­
matitidis is rare and frequently fatal, and mainly reported in immuno­
compromised patients or people with caspase recruitment domaincontaining protein 9 (CARD-9) deficiency. To date, a total of 22 cases,
in such patients, have been reported. Among them, 17 patients without
risk factors including deficiency or underlying conditions such as
contaminated steroid use, continuous ambulatory peritoneal dialysis,
acute lymphoblastic leukemia, and acquired immune deficiency syn­
drome, had poor clinical outcomes, and the other 5 cases with under­
lying diseases had relatively fair prognoses, suggesting that the

mortality rate was higher in patients without known risk factors than in
patients with underlying diseases. Recent studies have found that CARD9 deficiency is an autosomal-recessive primary immunodeficiency that
could increase susceptibility to candidiasis, especially CNS candidiasis
in healthy individuals [1]. We here describe the case of an otherwise
healthy patient with E. dermatitidis meningoencephalitis who achieved
clinical remission with high-dose long-term antifungal therapy in the
first 14 months. We performed a chromosome study of this patient and
his parents but found no CARD-9 deficiency.

Abbreviations: MR, magnetic resonance; CARD-9, caspase recruitment domain-containing protein 9; CSF, cerebrospinal fluid; ITS, internal transcribed spacer;
AIDS, acquired immune deficiency syndrome; IGRAs, interferon-γ release assays; TB, tuberculosis; MIC, minimum inhibitory concentration.
* Corresponding author.
E-mail addresses: yuhaiying@zju.edu.cn (H.-Y. Yu), qutingting@zju.edu.cn (T.-T. Qu), yq726226@163.com (Q. Yang), hjianhua0825@zju.edu.cn (J.-H. Hu),
jifang_sheng@zju.edu.cn (J.-F. Sheng).
https://doi.org/10.1016/j.jiac.2021.06.014
Received 20 April 2021; Received in revised form 8 June 2021; Accepted 14 June 2021

Available online 30 June 2021
1341-321X/© 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

H.-Y. Yu et al.

Journal of Infection and Chemotherapy 27 (2021) 1520–1524

Fig. 1. Brain magnetic resonance imaging showing cerebral pia mater enhancement and multiple lesions. A. Enhanced nodule in the left frontal region. B-D. Multiple
bilateral lesions in the cerebellum in T2WI and DWI phase, lesion enhancement of the left cerebellum in enhanced phase. T2WI: T2 weighted image; DWI: Diffusionweighted image.

Fig. 2. CSF smear and culture. A. CSF smear and hematoxylin-eosin staining revealing black fungal cells (original magnification × 400). B. CSF culture showing dark
fungal colonies of E. dermatitidis growing on Sabouraud Dextrose agar at 37 ◦ C.
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Table 1
Comparison of demographics and clinical outcomes of patients with CNS E.
dermatitidis infection in previous studies and in the present case.
Characteristic

Patients without known
risk factors
Country of origin
China
China
China
China
China
China
China
Angola
Korea
India
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Pakistan
Immunocompromised
patients with
predisposing factors
Chronic granulomatous
disease
Hematopoietic stem cell
transplant
Long-term steroid use
Long-term steroid use
Long-term steroid use

Fig. 3. Change curve of cerebrospinal fluid (CSF) pressure, cell counts, protein,
and glucose levels of the patient from September 5, 2017 to August 5, 2019.

2. Case report
A 15-year-old Chinese patient presented with chief complaints of
headache for 24 days and intermittent fever for 21 days before he was
admitted to our hospital. His body temperature ranged between 38 ◦ C
and 39.5 ◦ C, and he complained of headache and dizziness without
vomiting and physical tics. Magnetic resonance imaging (MRI) of the
brain revealed cerebral pia mater enhancement and multiple lesions in
the regions of basal ganglia and parencephalon (Fig. 1). The first lumbar
puncture showed a cerebrospinal fluid (CSF) pressure of 220 mmH2O,
and cerebrospinal fluid examination revealed moderate increases in CSF
protein levels and cell counts (mainly neutrophils initially and lym­
phocytes after therapy) and remarkable decreases in CSF glucose and
chloride levels (Table S1). He was first diagnosed with tuberculosis
meningitis and subsequently received empirical treatment (rifampin
0.45g, isoniazide 0.3g, pyrazinamide 1.5g, ethambutol 0.75g) for
tuberculosis meningoencephalitis with 10 mg dexamethasone per day.
However, his fever and headache worsened, and his interferon-γ release
assays for TB were negative. Moreover, he had high plasma and CSF
levels of [1–3]-β-glucan (302 pg/mL and 192 pg/mL, respectively). CSF
smear and hematoxylin-eosin staining revealed fungal cells, and the CSF
culture revealed the presence of a fungus that was different from Cryp­
tococcus and Candida (Fig. 2). It was identified as E. dermatitidis based on
its phenotype, and this was confirmed by internal transcribed spacer
(ITS) sequencing [2], the ITS region of 18S ribosomal DNA (rDNA) gene
was amplified with the general prime, and the sequence was compared
with known ITS gene sequences in the GenBank which referred to
Exophiala dermatitidis. The anti-tuberculosis treatment was stopped on
the 6th day, and he received amphotericin B (0.7 mg/kg) for 4 weeks.
However, the CSF culture continued to be positive. Further antifungal
susceptibility test showed sensitivity to voriconazole and posaconazole
and tolerance to fluconazole (voriconazole minimum inhibitory con­
centration [MIC] 0.25 mg/L, posaconazole MIC 0.25 mg/L, itraconazole
MIC 0.25 mg/L, amphotericin B MIC 1 mg/L, and fluconazole MIC 64
mg/L). We subsequently adjusted the treatment and administered 200
mg q12h voriconazole intravenously. After 12 weeks, his CSF culture
became negative, but his body temperature remained abnormal. MRI
examination revealed the development of new lesions in the basal
ganglia region. We administered high-dose voriconazole (300 mg q12h)
for another 12 weeks, and the CSF concentration of voriconazole ranged
from 4.1 μg/mL to 7.3 μg/mL. His body temperature gradually became
normal, and his headache and dizziness remitted. MRI examination
revealed disappearance of the lesions. However, his CSF examination
results remained abnormal, and the therapy was continued. After 14
months, he experienced adverse effects of the drug, such as obstinate
hypokalemia and liver dysfunction, and the therapy was adjusted to a
normal dose of voriconazole, then changed to posaconazole and

Age, Y
(Sex)

Outcome
(time from
diagnosis to
death, months

CARD-9
deficiency

Reference

15 (M)

Death (24)

no

8 (M)
3 (M)
23 (M)
30 (F)
19 (F)
3 (F)
5 (F)
28 (M)
21 (M)
17 (M)
30 (F)
5 (F)
26 (F)
19 (M)
10 (M)
20 (M)
70 (M)

Death (17)
Death (3)
Death (1)
Death (0.1)
Death (5)
Death (6)
Relapse
Death (0.5)
Cure (12)
Death (48)
Death (3)
Death (1)
Death (9)
Death (2)
Death (11)
Death (NA)
Death (0.5)

NA
NA
YES
NA
NA
NA
Yes
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

This
report
[21]
[17]
[20]
[16]
[16]
[16]
[7]
[12]
[13]
[14]
[14]
[14]
[14]
[14]
[14]
[14]
[15]

21 (F)

Cure

NA

[19]

Adult
(M)
77 (F)
61 (F)
71 (F)

Death

NA

[18]

Death
Cure
ND

NA
NA
NA

[22]
[22]
[22]

NA: not applicable; ND: not done.

amphotericin B, and eventually discontinued. During his last 2 months,
his condition worsened with slow reactions and intermittent seizures.
His intracranial pressure was more than 400 mmH2O, and MRI exami­
nation revealed hydrocephalus. The change curve of cerebrospinal fluid
pressure, cell counts, protein, and glucose levels are shown in Fig. 3. He
died after 2 years of therapy.
3. Discussion
Exophiala dermatitidis, (a type of black yeast) is an opportunistic
pathogen primarily responsible for skin infections [3]. It colonizes the
respiratory tract in approximately 6% of cystic fibrosis patients. Invasive
E. dermatitidis disease involves the lungs, peritoneum, blood, liver,
lymph nodes, and brain [4]. It is a rare and fatal infection that has
predominantly been reported in patients with predisposing factors such
as contaminated steroid use, continuous ambulatory peritoneal dialysis,
acute lymphoblastic leukemia, and acquired immune deficiency syn­
drome [5–7]. In contrast, CNS infection caused by E. dermatitidis is
extremely rare and primarily affects otherwise healthy people without
known risk factors. Most of the patients die despite receiving active
treatment [8]. Since 1980, 22 cases of E. dermatitidis meningoencepha­
litis have been reported worldwide (Table 1); among them 17 cases were
associated with no known risk factors. All 17 patients died or showed
relapse despite receiving active antifungal treatment, which indicate
specific gene defect maybe the pathogenesis.
Recent studies have shown that most patients with invasive
E. dermatitidis disease, which were not associated with any known risk
factors were of Asian descent (China, Japan, South Korea, Turkey, and
Pakistan) [12–17], and some of them were diagnosed with CARD-9
deficiency [8,20]. The latter is an autosomal-recessive primary
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Journal of Infection and Chemotherapy 27 (2021) 1520–1524

Fig. 4. Histological features of cervical lymph node biopsy specimen carried out by hematoxylin-eosin, Periodic acid-Schiff, and Gomori methenamine silver staining
techniques. Arrows indicate fungal agents. A-B. hematoxylin-eosin (HE) staining showing fungi surrounded by epithelioid and giant cell granuloma (original
magnification × 400). C. Periodic acid-Schiff (PAS) staining of the fungi (original magnification × 400). D. Gomori methenamine silver (GMS) staining of this area of
fungi (original magnification × 400).

immunodeficiency, which could increase susceptibility to candidiasis,
especially CNS candidiasis. Inherited CARD-9 deficiency was recently
reported in otherwise healthy persons with severe invasive fungal in­
fections caused by Candida, Phialophora, Exophiala, and Trichophytoon,
including meningoencephalitis [9].
CARD-9 is an adaptor molecule that mediates intracellular signaling
downstream of innate pattern recognition receptors involved in anti­
fungal immunity [10]. Despite treatment with strong antifungal agents,
the infection may not be controlled. Most of the patients had disease
relapse or even died. Therefore, we sequenced CARD-9 gene by Exome
Sequencing of the patient and his parents in the present case, but found
no mutants.
The patient was otherwise healthy without systemic diseases. How­
ever, 5 years ago, when he was 10 years old; he had recurrent fever and
multiple cervical lymphadenectasis for 2 months, and marked persistent
eosinophilia with up to 60% eosinophils in his peripheral blood without
parasitic infection. High levels of plasma [1–3]-β-glucan (890 pg/mL)
were observed, and fungal infection was identified by cervical lymph
node biopsy. Pathological examination revealed fungal hyphae in the
slice (Fig. 4). He subsequently underwent treatment with 400 mg flu­
conazole per day for 1 year, and his body temperature and eosinophil
count gradually returned to normal. The relationship between the two
invasive fungal infections in this case remains unknown, which implies a
specific deficiency in the antifungal immune response of this otherwise
healthy patient. Gene deficiency is the most probable explanation in
most cases, and CARD-9 deficiency may have enabled a severe, invasive,
and fatal fungal infection; although this was not the case with our pa­
tient. Patients with CARD-9 deficiency have defective neutrophils,

which are involved in the intracellular killing of the yeast Candida, and
severely reduced levels of circulating Th17 cells and TNF-α [1]. The
patient in the present case recovered from lymph node fungal infection
but not from CNS E. dermatitidis infection; different outcomes were
observed due to different infection sites and fungal species [11]. Despite
the in vitro susceptibility to antifungal agents, the infection may relapse
and can be potentially fatal. Optimal treatment needs to be defined for
E. dermatitidis meningoencephalitis.
Ethics approval
This study obtained approval from the Ethics Committee of the First
Affiliated Hospital, Zhejiang University.
Funding source
The funding source had no involvement in study design; in the
collection, analysis and interpretation of data; in the writing of the
report; and in the decision to submit the article for publication.
Authorship statement
Hai-Ying Yu was responsible for the patient’s treatment and
consulting literature. Ji-Fang Sheng was the chief investigator and was
responsible for the treatment. Ting-Ting Qu and Qing Yang were spe­
cialists in pathogen culturing and identification. Jian-Hua Hu was
responsible for patient follow-up. All authors contributed to the writing
of the final manuscript.
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Journal of Infection and Chemotherapy 27 (2021) 1520–1524

Informed consent

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The patient provided signed informed consent for his data to be
analyzed and reported.
Declaration of competing interest
None.
Acknowledgements
This work was supported by a research grant from the Chinese Na­
tional Thirteenth Five Years Project in Science and Technology
(2017ZX10202201).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jiac.2021.06.014.
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