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Journal of Clinical Microbiology, September 2000, p. 3460-3462, Vol. 38, No. 9
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Mixed Infection Caused by Two Species of
Fusarium in a Human Immunodeficiency Virus-Positive
Patient
Josep
Guarro,1,*
Marcio
Nucci,2
Tiyomi
Akiti,2 and
Josepa
Gené1
Unitat de Microbiologia, Facultat de Medicina
i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus,
Spain,1 and Laboratório de
Micología, Hospital Universitário Clementino Fraga Filho,
Universidade Federal do Rio de Janeiro, Rio de Janeiro,
Brazil2
Received 23 February 2000/Returned for modification 13 April
2000/Accepted 9 June 2000
 |
ABSTRACT |
We report on a case of mixed infection caused by two species of
Fusarium in a human immunodeficiency virus-positive patient with lymphoma who was neutropenic due to chemotherapy. The patient showed the typical signs of a disseminated fusarial infection, with
Fusarium solani isolated from skin lesions and F. verticillioides isolated from blood. The report discusses how
difficult it is to make an accurate diagnosis when an immunosuppressed
patient is infected with more than one fungal species, especially when the species are morphologically very similar.
| |
TEXT |
Disseminated fusarial infections are
associated with a high rate of mortality. Their treatment constitutes a
difficult challenge for modern medicine. Approximately eight species of
Fusarium are recognized as opportunistic pathogens that
cause disseminated infections in the compromised host (6).
The recovery of two Fusarium species from the same patient
is unusual and warrants special attention by clinical microbiologists.
This report describes a fatal case of fusarial infection in a
neutropenic human immunodeficiency virus (HIV)-positive patient with
lymphoma from whom Fusarium solani and F. verticillioides, the two most common species of this genus
pathogenic for humans, were isolated. To our knowledge, this is the
first published report of simultaneous infection with two species of
Fusarium.
Case report.
A 50-year-old Brazilian man was admitted to the
Hospital Universitário Clementino Fraga Filho because of fever
and neutropenia after chemotherapy for high-grade non-Hodgkin's
lymphoma. He had been severely neutropenic for 11 days and had received
ciprofloxacin, amikacin, fluconazole, and granulocyte
colony-stimulating factors (G-CSF). He was seropositive for HIV.
Physical examination revealed pallor, mild jaundice, moderate
mucositis, and fever (axillary temperature, 37.8°C). The patient's
hemoglobin concentration was 11.2 g/dl, the leukocyte count was
600/mm3 with 150 neutrophils/mm3, and the
platelet count was 8,000/mm3. Two blood samples were
collected for culture, G-CSF was continued, and ceftazidime, amikacin,
and vancomycin were administered. Two days later empirical amphotericin
B (0.5 mg/kg of body weight daily) and metronidazole were added because
of persistent fever and worsening of the mucositis. Two days later
numerous erythematous lesions measuring 1 to 2 cm appeared on the arms,
abdomen, and right leg. The patient complained of myalgia. A biopsy
sample of one of the skin lesions was obtained for histopathologic
examination and culture. In addition, another two blood samples were
taken and the amphotericin B dosage was increased to 1 mg/kg daily. Blood samples were processed as follows. Each blood sample was inoculated into two bottles containing brain heart infusion broth, and
the bottles were examined daily for at least 4 weeks. The bottles were
incubated at 37°C, and blind subcultures were made after 6 to 24 h of incubation or whenever examination of the bottles suggested growth
of microorganisms. The subcultures were made by taking 0.5 ml of the
liquid from the bottle with disposable syringes and inoculating it into
four tubes containing solid media: brain heart infusion agar (Merck
KgaA, Darmstadt, Germany), Sabouraud dextrose agar (Difco Laboratories,
Detroit, Mich.), mycobiotic agar (Difco), and niger seed agar. The
tubes were incubated at room temperature. The fragments of the skin
biopsy specimen were sliced, inoculated into four tubes containing the
same solid media used for blood, and also incubated at room
temperature. Numerous white colonies of a Fusarium sp. grew
from all blood samples and from the biopsied tissue. However, in the
histologic study with hematoxylin and eosin, Giemsa, and Gomori
methenamine silver stains, there was only mild inflammation with
mononuclear cells in the dermis, and no fungal elements were detected.
The dosage of amphotericin B was increased to 1.5 mg/kg daily. Five
days later the patient recovered from the neutropenia and the skin
lesions were a little better. Two days later, the patient suddenly lost
consciousness, developed respiratory and circulatory arrest, and died.
An autopsy was refused.
Because all colonies were apparently identical, only two isolates were
kept for the identification of the Fusarium species, one
from the biopsy tissue cultures and the other from the blood cultures.
For that purpose, the subcultures of both isolates were referred to the
Microbiology Unit of the Faculty of Medicine at the Rovira i Virgili
University in Reus, Spain.
Diagnosis of mycological infection.
The isolate from the
biopsy material was designated FMR 6323 and that from blood was
designated FMR 6488. Both were subcultured on potato dextrose agar
(PDA; Difco) and oatmeal agar (OMA; 30 g of oat flakes, 1 g
of SO4Mg · 7H2O, 1.5 g of
PO4H2K, 15 g of agar, 1,000 ml of tap
water; homemade) and incubated in the darkness at ca. 25°C.
Colonies of FMR 6323 on PDA attained diameters of 35 to 36 mm after 4 days, with a greyish white, dense, and floccose aerial
mycelium and a
bluish brown reverse. Colonies grown on OMA showed
a growth rate
similar to those of colonies grown on PDA, but the
aerial mycelium was
white and sparse. Macroconidia were abundantly
produced after 7 days on
both media from confluent, cream-colored
sporodochia. These were
hyaline, usually moderately curved, three-septate,
and 30 to 43 µm
long by 4 to 5.5 µm wide. Microconidia were also
abundantly produced
and disposed in slimy heads on monophialides.
These were also hyaline
and usually oval and nonseptate, measuring
7 to 15 µm by 2 to 4.5 µm. Chlamydospores were also produced,
both singly and in pairs. From
these features, the isolate was
identified as
F. solani
(Fig.
1). Colonies of FMR 6488 developed
more rapidly than those of FMR 6323 on PDA and OMA and reached
diameters of 47 and 55 mm, respectively, after 4 days. On PDA,
the
aerial mycelium was first white and cottony but soon became
white and
vinaceous. Colonies on OMA were also vinaceous, but
these were powdery
due to the abundant production of microconidia
in chains. Microconidia
were usually clavate with a slightly truncate
base, were 5 to 10 µm
long by 2 to 3 µm wide, and were produced
only from monophialides.
Macroconidia and chlamydospores were
not produced. These typical
colonies and the microscopic features
of the microconidia identified
the isolate as
F. verticillioides (
F. moniliforme) (Fig.
2). Both names
are widely used in the medical
literature, although in recent molecular
studies it has been proved
that
F. moniliforme is a synonym
of
F. verticillioides, and the
latter name has priority over
the former (
16).
F. solani and
F. verticillioides can easily be differentiated mainly by the
arrangement of the microconidia on the conidiogenous cells and
the
colony features after at least 5 days of incubation (
6).
Both are the most common species in disseminated infections (
2,
6).
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FIG. 1.
F. solani FMR 6323. (A) Phialide.
Magnification by scanning electron microscopy, ×1,870. (B)
Macroconidia. Magnification by scanning electron microscopy, ×1,650.
(C) Chlamydospores. Magnification by scanning electron microscopy,
×2,500.
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FIG. 2.
F. verticillioides FMR 6488. (A) Chains of
microconidia. Magnification, ×160. (B) Conidiophore. Magnification by
scanning electron microscopy, ×2,320.
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|
The case described here was typical of an invasive fusarial infection,
i.e., fever refractory to antibacterial drugs, numerous
skin lesions,
and myalgias (
2). However, this is the first
patient from
whom two different species of
Fusarium have been
isolated.
Neither of the two most commonly described portals of
entry for the
infection (skin and airways) (
7) was evident
in our
patient.
Mixed fungal infections are uncommon (
3,
11,
14,
17,
20,
22).
Fusarium species have also been involved in
concomitant
infections, especially in immunocompromised patients, but
with
species of other genera (
10,
21). When mixed infections
are
caused by fungi from different species, it is relatively easy
to
determine that more than one species is involved. However,
the colonies
produced by the different species of
Fusarium are
often very
similar, especially during the first few days of incubation
(Fig.
3), and they are difficult to
differentiate when they are
present in the same sample. Given that it
can be difficult to
discriminate between
Fusarium colony
types at an early stage of
growth, it was perhaps fortuitous that one
colony of
F. solani was subcultured from the primary culture
of the skin biopsy specimen
and one colony of
F. verticillioides was subcultured from the
primary blood culture.
Both subcultures were referred to the Microbiology
Unit as two isolates
of the same strain of
Fusarium sp.; however,
when we
examined both fungi we noticed that they belonged to different
species.
Unfortunately, we could not obtain more samples because
the patient had
died. In this case no fungal structures were observed
in the
histological study of the biopsied material. Although the
observation
of hyphal elements in tissue is very important in
the diagnosis of
fungal infections, they are not always detected
in disseminated
fusarial infections (
13). Additionally, we must
remember
that the histological appearance of
Fusarium species
is
variable and can mimic that of several other opportunistic
molds.
Therefore, even when fungal structures compatible with
species of
Fusarium are observed, cultures are required to confirm
the
diagnosis and for species identification. This is important
because
different virulences among species have clearly been demonstrated
in
Fusarium. Using a murine model, we proved that
F. solani was
clearly more pathogenic than the other species involved
in disseminated
infections, i.e.,
F. oxysporum,
F. verticillioides, and
F. proliferatum (
12),
and moreover,
F. solani is the most common species causing
fatal infections in humans (
7). Detection of only one
species
when two or more are present may result in false hope and
erroneous
treatment. The species detected may also be less virulent
than
the other one(s) present. For our patient, knowing that two
species
were involved would not have affected the outcome for the
patient
because the few antifungal drugs available are not efficacious
against
Fusarium either in vitro (
19) or in vivo
(
8). However,
this information could be extremely useful in
other cases, for
instance, in
Scedosporium infections
(
Scedosporium prolificans and
S. apiospermum show
very different susceptibilities to antifungal
agents) (J. Guarro, J. Cano, J. Gené, M. Solé, and A. J. Carrillo,
Abstr. 14th Int. Soc. Hum. Anim. Mycol. Congr., p. 84, 2000) and
in
Paecilomyces infections (the two most common
Paecilomyces species,
Paecilomyces variotii and
P. lilacinus, also show very different
antifungal
susceptibilities) (
1).
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FIG. 3.
Colonies of F. solani (A) and F. verticillioides (B) on PDA at 25°C after 2 days of incubation.
|
|
In HIV-infected patients the typical opportunistic fungi such as
Candida albicans,
Cryptococcus neoformans,
Histoplasma capsulatum,
and
Coccidioides immitis
are found regularly, as are other, less
common ones like
Sporothrix schenckii and
Penicillium marneffei (
18). However,
Fusarium species which are
isolated in increasing
number from immunosuppressed hosts (mainly
leukemic patients)
are rarely found in HIV-positive or AIDS patients.
The only previously
reported cases were localized infections that
affect the lung
(
9), heart (E. Stool, J. Gathe, Jr., D. Piot, G. del Junco,
and T. Anderson, 7th Int. Conf. AIDS, abstr. MB
2390, 1991), and
eyes (
5), although they may also have
caused onychomycosis
in these patients (
4). To our
knowledge, this is the first
case of disseminated fusarial infection in
an HIV-positive patient.
In addition, the patient was diagnosed as
having a lymphoma and
was neutropenic due to chemotherapy, a setting
very similar to
those for the majority of patients with disseminated
fusariosis
reported so far (
15). We therefore think that
neutropenia induced
by chemotherapy rather than the immunosuppression
due to HIV infection
played a major role in the development of this
infection.
The case described here illustrates the importance of culture and of
the accurate identification of the isolates, especially
in
immunosuppressed patients, when more than one species may be
present.
Medical microbiologists should be aware of this
possibility.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Unitat de
Microbiologia, Departament de Ciències Mèdiques
Bàsiques, Facultat de Medicina i Ciències de la Salut,
Universitat Rovira i Virgili, Carrer Sant Llorenç 21, 43201-Reus,
Tarragona, Spain. Phone: 34 977759359. Fax: 34 977759322. E-mail:
umb{at}fmcs.urv.es.
| |
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Journal of Clinical Microbiology, September 2000, p. 3460-3462, Vol. 38, No. 9
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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