Fatal Cerebral Phaeohyphomycosis in an Immunocompetent Individual Due to Thielavia subthermophila

Abstract

We report the first case of fatal brain infection in an Indian farmer caused by Thielavia subthermophila, a dematiaceous thermophilic fungus in the order Sordariales, and present a review of previous infections from this order. The patient failed amphotericin B therapy combined with surgical
excision despite the drug's low MICs in vitro.

Full text

JOURNAL OF CLINICAL MICROBIOLOGY, June 2011, p. 2336–2341 Vol. 49, No. 6
0095-1137/11/$12.00 doi:10.1128/JCM.02648-10
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Fatal Cerebral Phaeohyphomycosis in an Immunocompetent Individual
Due to Thielavia subthermophila
䌤
Hamid Badali,
1,2
Jagdish Chander,
3
Ashish Gupta,
4
Hena Rani,
3
Rajpal Singh Punia,
5
G. Sybren De Hoog,
2
and Jacques F. Meis
6
*
Department of Medical Mycology and Parasitology, School of Medicine/Molecular and Cell Biology Research Centre,
Mazandaran University of Medical Sciences, Sari, Iran
1
; CBS-KNAW Fungal Biodiversity Centre, Utrecht, Netherlands
2
;
Departments of Microbiology,
3
General Surgery,
4
and Pathology,
5
Government Medical College Hospital, Chandigarh,
India; and Department of Medical Microbiology and Infectious Diseases,
Canisius Wilhelmina Hospital, Nijmegen, Netherlands
6
Received 30 December 2010/Returned for modification 17 February 2011/Accepted 4 March 2011
We report the first case of fatal brain infection in an Indian farmer caused by Thielavia subthermophila,a
dematiaceous thermophilic fungus in the order Sordariales, and present a review of previous infections from
this order. The patient failed amphotericin B therapy combined with surgical excision despite the drug’s low
MICs in vitro.
CASE REPORT
A 39-year-old male presented in the Emergency Depart-
ment of Government Medical College Hospital (GMCH),
Chandigarh, India, with complaints of multiple episodes of
generalized tonic-clonic seizures for the previous 10 days. He
experienced, in addition to the seizures, uncontrolled move-
ments of his limbs and rolling of his eyes, incontinence of
urine, and production of foam from his mouth. There was a
history of fever for 2 days, associated with an attack of seizures.
He was a resident of Ambala (Haryana State, northern India)
and a farmer by occupation, with a low socioeconomic status.
He was first admitted to a local hospital in Ambala and was
subsequently transported to the GMCH. In the past, he never
had headaches or any other significant complaints. There was
no history of any trauma, roadside accidents, near-drowning,
or similar predisposing factors.
On examination, the patient was having an altered senso-
rium and was disoriented, with a Glasgow coma score of
E2V2M4. On the basis of generalized tonic-clonic seizures, a
presumptive diagnosis of meningioma was made. His chest X
ray and electrocardiogram (ECG) were normal. A lumbar
puncture was done, and cerebrospinal fluid (CSF) was sent for
cytological, biochemical, and microbiological examination.
Gram staining, Ziehl-Neelsen (ZN) staining, and fungal
smears of CSF were negative, and there was no growth of
either bacteria or fungi. The cytological and biochemical ex-
amination of CSF was noncontributory. The other laboratory
investigations revealed that his hemogram, white blood cells,
serum electrolytes, liver function, and glucose concentration
were within normal ranges.
A magnetic resonance image (MRI) of his brain showed a
large, supratentorial, intracranial, right-frontotemporal, space-
occupying lesion (7.0 by 7.5 by 8.6 cm) and also small compo-
nents devoid of frank edema alongside the frontal part of the
falx cerebri, suggestive of meningioma in the right sphenoidal
wing (Fig. 1A and B). Therefore, right-frontotemporal crani-
otomy was done for excision of the intracranial mass, which
intraoperatively showed a white, cheesy, and gelatinous sub-
stance, suggestive of infective pathology rather than of menin-
gioma. The excised intracranial mass was sent for histopatho-
logical and microbiological examination. Direct microscopy
revealed neither Mycobacterium nor other bacteria with Ziehl-
Neelsen (ZN) staining or Gram staining, respectively, but
KOH preparations showed septate, branched fungal hyphae
(Fig. 2A). Histopathological examination with periodic acid-
Schiff (PAS) staining showed fungal granulomas in the brain
parenchyma centered around blood vessels. Granulomas were
made up of epithelioid cells with giant cells and collections of
neutrophils. These granulomas and giant cells contained sep-
tate fungal hyphae, and blood vessels showed evidence of vas-
culitis. There was also angioinvasion by the fungal hyphae;
however, necrosis was not seen (Fig. 2B). Fungal culture was
done with Sabouraud’s dextrose agar (SDA; HiMedia, Mum-
bai, India) with and without antibiotics and incubated at both
37°C and 22°C. The bacterial and mycobacterial cultures re-
mained sterile. On the second day of incubation, SDA plates
showed mycelial growth at both 37°C and 22°C. Lactophenol
cotton blue (LCB) mounts of the black fungal growth showed
sterile, dematiaceous hyphae which did not allow morpholog-
ical identification.
The patient was treated with intravenous amphotericin B
deoxycholate (1 mg/kg of body weight/day), but his condition
deteriorated rapidly and he developed respiratory distress, for
which a tracheostomy was necessary. Despite antifungal ther-
apy, the patient died 2 weeks later due to cardiac arrest and
respiratory failure.
Mycology. The fungal culture was deposited in the reference
collection of CBS-KNAW, Utrecht, Netherlands, under acces-
sion number CBS 125981. Stock cultures were maintained on
slants of 2% malt extract agar (MEA; Difco, Leeuwarden,
* Corresponding author. Mailing address: Department of Medical
Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital,
Weg door Jonkerbos 100, 6532 SZ Nijmegen, Netherlands. Phone: 00
312 43657514. Fax: 00 312 43657516. E-mail: j.meis@cwz.nl.
䌤
Published ahead of print on 16 March 2011.
2336

Netherlands) and oatmeal agar (OA) at 24°C (14). Colonies
showed rapid growth and were flat and velvety to floccose, with
an olivaceous-black reverse on OA (Fig. 3A). Smears from old
cultures were prepared in lactic acid and in sterile water and
examined with a Nikon Eclipse 80i microscope equipped with
a Nikon digital-sight DS-Fi1 camera. Septate, branching, dark
olivaceous hyphae were observed. Supplementary cultures
were prepared on MEA, potato carrot agar (PCA; Difco),
potato dextrose agar (PDA), and oatmeal agar (OA) with or
without lupine stems and incubated at 25, 35, 42, 45, and 50°C
for a period of 3 weeks under alternate near-UV light to
suppress the growth of aerial hyphae and induce adequate
ascoma formation (14). After 2 weeks of incubation, scattered
black ascomata were observed on all media tested (Fig. 3B).
Walls of the ascomata consisted of textura epidermoidea (i.e.,
of jigsaw-shaped cells [14]) coated with dark hyphae. The
brown, fusiform ascospores were single celled (10 to 12 by 7.5
to 8.5 ␮m) and had a characteristic subapical germ pore mea-
suring 1 to 1.5 ␮m (Fig. 3C to E). Thermotolerance tests
showed that the isolate grew rapidly at both 35°C and higher
temperatures of 42°C, 45°C, and 50°C. Subsequently, the fun-
gus was phenotypically identified as a Thielavia species. Se-
quencing was used to further identify it to the species level.
For molecular analyses, the fungus was grown on 2% MEA
plates, and DNA was extracted using an UltraClean microbial
DNA isolation kit (MO BIO, Carlsbad, CA) according to the
FIG. 1. Coronal (A) and axial (B) MRI images of the brain demonstrating a large, supratentorial, intracranial, right-frontotemporal, space-
occupying lesion and also small, left-frontal components devoid of frank edema on both sides of the falx cerebri.
FIG. 2. (A) Septate hyphae observed in a KOH wet mount; (B) photomicrograph of brain parenchyma showing granuloma and septate hyphae
(PAS staining; magnification, ⫻400).
VOL. 49, 2011 CASE REPORTS 2337

manufacturer’s instructions. PCR amplification and sequenc-
ing were carried out according to the method of Badali et al.
(7). Briefly, the universal fungal primer pairs V9G (5⬘-TTAC
GTCCCTGCCCTTTGTA-3⬘)/LS266 (5⬘-GCATTCCCAAAC
AACTCGACTC-3⬘) and LROR/LR7 were used for amplifica-
tion of internal transcribed spacer (ITS) ribosomal DNA
(rDNA) and 28S rRNA (nucLSU), respectively. PCRs were
performed on a GeneAmp PCR system 9700 (Applied Biosys-
tems, Foster City, CA) in 50-␮l volumes containing 25 ng
template DNA, 5 ␮l reaction buffer (0.1 M Tris-HCl, pH 8.0,
0.5 M KCl, 15 mM MgCl
2
, 0.1% gelatin, 1% Triton X-100), 0.2
mM each deoxynucleoside triphosphate (dNTP), and 2.0 U
Taq DNA polymerase (ITK Diagnostics, Leiden, Nether-
lands). Amplification of ITS and nucLSU was performed with
cycles of 2 min at 94°C for primary denaturation, followed by
35 cycles at 94°C (45 s), 52°C (30 s), and 72°C (120 s), with a
final 7-min extension step at 72°C. Amplicons were purified
using GFX PCR DNA and a gel band purification kit (GE
Healthcare, Ltd., Buckinghamshire, United Kingdom). Se-
quencing was performed as follows: 95°C for 1 min, followed
by 30 cycles consisting of 95°C for 10 s, 50°C for 5 s, and 60°C
for 2 min. Reaction mixtures were purified with Sephadex G-50
fine (GE Healthcare Bio-Sciences AB, Uppsala, Sweden), and
sequencing was done on an ABI 3730xl automatic sequencer
(Applied Biosystems, Foster City, CA). Sequence data ob-
tained in this study were adjusted using Lasergene SeqMan
software (DNAStar, Inc., Madison, WI). Sequences were com-
pared with entries in GenBank and by using local BLAST
searching in a molecular database maintained at the CBS and
validated by ex-type strains. Isolate CBS 125981 was identified
as Thielavia subthermophila by 98.98% and 100% identities
in its ITS rDNA and nucLSU regions, respectively, with
GenBank submissions, which included accession number
AJ271575.1 from the recent revision of Thielavia by Stchigel et
al. (28), and by 99.6% identity with CBS 509.74, the ex-type
strain of T. subthermophila. This led to the final diagnosis of
the infection as a cerebral phaeohyphomycosis due to Thielavia
subthermophila.
In vitro antifungal susceptibility testing was performed using
the M38-A2 reference method of the Clinical and Laboratory
Standards Institute (CLSI) by using a broth microdilution for-
mat (13, 16). Briefly, ascospore suspensions were prepared
FIG. 3. Thielavia subthermophila (CBS 125981). (A) A culture on oatmeal agar at 42°C after 2 weeks in darkness with lupine stem grew rapidly
and was flat and velvety or floccose, with an olivaceous-black reverse. (B and C) Scattered black ascomata developing within the hyphae. (D and
E) The brown, fusiform ascospores are single celled (10 to 12 by 7.5 to 8.5 ␮m) and have a characteristic subapical germ pore measuring 1 to 1.5
␮m. Scale bars, 10 ␮m.
2338 CASE REPORTS J. CLIN.MICROBIOL.

from ⬎3-week-old cultures on OA with lupine stems (14) at
37°C by gently scraping the surfaces of mature colonies with a
sterile moistened cotton swab. If large aggregates existed, they
were allowed to settle for several minutes, the homogenous
suspension of asci and ascospores was then transferred to
sterile tubes, and the asci and ascospores in the supernatants
were counted with a hemocytometer. Broth dilutions were
done in RPMI 1640 medium with L-glutamine, without bicar-
bonate, and buffered with 0.165 M morpholinepropanesulfonic
acid (MOPS). Paecilomyces variotii (ATCC 22319), Candida
parapsilosis (ATCC 22019), and Candida krusei (ATCC 6258)
were used as quality control organisms (13). The isolate
showed the following antifungal susceptibility profile: ampho-
tericin B, 0.03 ␮g/ml; fluconazole, 8 ␮g/ml; itraconazole, 0.016
␮g/ml; voriconazole, 0.016 ␮g/ml; posaconazole, 0.016 ␮g/ml;
and isavuconazole, 0.016 ␮g/ml. The minimum effective con-
centrations of caspofungin and micafungin were 4 and 0.25
␮g/ml, respectively.
Discussion. During recent decades, the diversity of fungal
agents causing systemic disease has increased dramatically,
especially in immunocompromised hosts, patients using broad-
spectrum antibiotics, or patients with severe underlying dis-
eases or undergoing solid organ transplantation. Melanized
(dematiaceous) fungi are particularly significant because they
infect not only debilitated hosts but also apparently healthy
individuals, giving infections which range from mild cutaneous
infections to fatal brain disease (12, 15, 19, 20, 22, 29). Primary
cerebral phaeohyphomycosis is a rare disorder characterized
by black necrotic tissue and the production of pus, frequently
occurring in humans without known predisposing factors or
immunodeficiency (19, 22, 26). The infection is recognized as a
disease associated with high mortality and ultimately a poor
prognosis despite the application of surgery and antifungal
therapy (12, 22). If untreated, the infection may lead to death
within weeks, months, or, occasionally, years. The majority of
etiological agents belong to a single order of known environ-
mental fungi, the Chaetothyriales (e.g., Cladophialophora,Exo-
phiala,Rhinocladiella, and Fonsecaea). Occasionally species
from other orders are involved, such as Sordariales (Chaeto-
mium), Pleosporales (Bipolaris,Exserohilum), Xylariales (Nodu-
lisporium), and Botryosphaeriales (Neoscytalidium) (22).
Thielavia is a common genus of environmental ascomycetes
belonging to the family Chaetomiaceae in the order Sordariales.
The genus is characterized by spherical, nonostiolate ascomata
with a thin peridium (ascoma wall), producing one-celled,
darkly pigmented ascospores (14, 25, 31, 32). Taxonomy and
phylogeny of Thielavia have been the subject of some confu-
sion, because optimal markers for species distinction have not
yet been established (28). A morphotaxonomic revision by von
Arx et al. (31, 32) described 14 species, but developments in
molecular techniques revolutionized species concepts. Thiela-
via subthermophila (not to be confused with Thielavia thermo-
phila Fergus & Sinden) was introduced by Mouchacca (24) for
a species from desert soil which showed good growth at 45°C.
The species is further characterized by the presence of pig-
mented mycelium and brownish-black, hairy ascomata. Thiela-
via gigaspora (25), Thielavia arenaria,Thielavia hyrcania, and
Thielavia microspora (31) are distinguished by the criteria of
ascospore size and position of germ pores (28). Thielavia spe-
cies have rarely been proven to be involved in human infec-
tions. Bourbeau et al. (11) described a disseminated infection
due to Myceliophthora thermophila, the anamorph of Thielavia
heterothallica, and Theoulakis et al. (29) reported a keratitis
due to T. subthermophila in a 10-year-old girl. Our patient is
the first reported case of severe systemic infection due to T.
subthermophila. Identification by a molecular approach like
sequencing of ITS rDNA and comparison to sequences in
GenBank is the best and most simple approach for the difficult
identification of these sporulating fungi. This species is an
addition to the list of potential agents of primary brain ab-
scesses in apparently healthy individuals, which includes its
black-yeast-like relatives Cladophialophora bantiana,Exo-
phiala dermatitidis,Fonsecaea monophora, and Rhinocladiella
mackenziei (7–9, 27). Primary or secondary brain infections are
distinguished by their modes of infection, either by supposed
hematogenous spread from an unrecognized pulmonary focus
or through direct extension from an adjacent focus, e.g., in
paranasal sinuses or after a penetrating trauma to the head
(12, 19, 21, 27).
Thielavia is closely related to Chaetomium (Sordariales,
Chaetomiaceae), a large genus of saprobic ascomycetes that are
widespread in soil, in plant debris, and on wood. Both species
have been recovered during air surveys in jute fields in India
(30), suggesting that the probable source for our patient, a
farmer, was airborne. Chaetomium globosum,Chaetomium
atrobrunneum,Chaetomium funicola, and Chaetomium stru-
marium have occasionally been encountered in a wide variety
of human infections, such as onychomycosis, sinusitis, pneu-
monia, and cerebral abscess. Fatal cerebral infection was re-
peatedly reported in intravenous drug users, with a high mor-
tality despite the administration of antifungal combination
therapy (1). The disorder may be underdiagnosed, because
many ascomycetes in the Sordariales do not produce ana-
morphs and may appear as sterile mycelium. In addition, the
correct identification of species described 20 years ago can be
doubted, as these isolates have not been reexamined with mo-
lecular methods. We have the impression that members of the
Sordariales target relatively frequently the cerebrum (22). The
optimal temperature for most Chaetomium species lies be-
tween 25 and 35°C (10, 23, 28), while those that have been
reported to cause invasive infection grow very well above 35°C
to 45°C. The invasive infections due to Thielavia and Chaeto-
mium species reported to date are summarized in Table 1.
Cases of brain infection due to C. strumarium have occurred
in intravenous drug abusers and in patients with hematologic
malignancies and solid organ transplantation (1). The outcome
was generally poor. Al-Aidaroos et al. (4) reported fatal inva-
sive infections in two immunocompromised pediatric patients
due to C. atrobrunneum. The present study adds another ther-
mophilic member of the Sordariales (T. subthermophila)tothe
list of potential agents of phaeohyphomycotic brain infections.
The keratitis due to T. subthermophila reported by Theou-
lakis et al. (29) was successfully treated with topical ampho-
tericin B and oral voriconazole. Treatment of cerebral phae-
ohyphomycosis generally includes surgical debridement,
combined with antifungal therapy and/or immune enhance-
ment. Although the etiologic agent in our case had a low in
VOL. 49, 2011 CASE REPORTS 2339

vitro MIC of amphotericin B, the patient died despite ampho-
tericin B therapy. Murine studies showed no benefit from am-
photericin B in cerebral phaeohyphomycosis due to poor pen-
etration into the central nervous system (2), which may explain,
in part, the treatment failure. Currently, there is no accepted
standard therapy for brain infections by melanized fungi, but in
vitro data (7, 8, 9) and one clinical study (3) suggest that
posaconazole may be a potential choice.
Nucleotide sequence accession numbers. The ITS rDNA
and nucLSU sequences from isolate CBS 125981 determined
in this study have been deposited in GenBank under accession
numbers HM448441 and HM448442, respectively.
This study was supported by a grant (no. 13081) to H. Badali from
the Ministry of Health and Medical Education of the Islamic Republic
of Iran and the School of Medicine, Mazandaran University of Medical
Sciences, Sari, Iran. J. F. Meis received grants form Astellas, Merck,
Basilea, and Schering-Plough. He has been a consultant to Astellas,
Basilea, and Merck and received speaker’s fees from Merck, Pfizer,
Schering-Plough, and Janssen Pharmaceutica. All other authors report
no conflicts of interest.
We are most grateful to Walter Gams for suggestions with respect to
phenotypic identification.
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a
Agent Age (yr) Sex Host status Site of infection Therapy Outcome Reference
T. subthermophila 39 M Healthy Brain AmB Died This study
10 F Healthy Cornea Ciprofloxacin, tobramycin,
AmB, cefazolin
Cured 28
C. strumarium 20 M IVDA Brain Ceftriaxone, penicillin,
acyclovir
Died 1
25 M IVDA Brain Amoxicillin, acyclovir,
AmB, rifampin,
isoniazid
Died 1
28 M IVDA Brain Oxacillin, cefotaxime,
metronidazole
Died 1
C. atrobrunneum 31 M Multiple myeloma,
allogeneic BMT
Brain, lung AmB, ITC Died 17
32 M Renal transplant Brain Unknown Died 5
12 M AML CSF, brain AmB, itraconazole, L-
AmB
Died 4
⬍1 M Anemia, pancytopenia Lung Piperacillin-tazobactam,
gentamicin, AmB,
L-AmB, ITC
Died 4
C. globosum 19 F Lymphoma/autologous
BMT
Lung pleura Imipenem, vancomycin,
amikacin, AmB
Died 21
24 M ALL Lung AmB Died 18
C. perlucidum 78 F Asthma, chronic
bronchiectasis
Lung RML lobectomy Cured 10
47 F Leukemia, umbilical cord
blood transplant
Multiple organs L-AmB Died 10
Chaetomium sp. 19 M AML Lung L-AmB Died 33
73 F None Left maxillary
sinus
Infundibulectomy Cured 6
a
M, male; F, female; BMT, bone marrow transplant recipient; RML, right middle lobe; IVDA, intravenous drug abuser; AML, acute myelogenous leukemia patient;
ALL, acute lymphocytic leukemia patient; AmB, amphotericin B; ITC, itraconazole; L-AmB, liposomal amphotericin B.
2340 CASE REPORTS J. CLIN.MICROBIOL.

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