REVIEW ARTICLE
Disseminated Phaeohyphomycosis:
Review of an Emerging Mycosis
Sanjay G. Revankar,1 Jan E. Patterson,2 Deanna A. Sutton,3 Renee Pullen,2 and Michael G. Rinaldi3,4
1
Dallas Veterans Administration Medical Center and Department of Medicine, University of Texas Southwestern Medical Center, Dallas,
Departments of 2Medicine and 3Pathology, University of Texas Health Science Center at San Antonio, and 4Audie L. Murphy Veterans
Administration Medical Center, San Antonio, Texas
Disseminated phaeohyphomycosis is an uncommon infection caused by dematiaceous fungi, although the
number of case reports about this infection has been increasing in recent years. A total of 72 cases are reviewed.
Scedosporium prolificans is by far the most common cause. The presence of melanin in their cell walls may
be a virulence factor for these fungi. The primary risk factor is decreased host immunity, although cases in
apparently immunocompetent patients have been reported. Eosinophilia was seen in 11% of cases. Endocarditis
is mostly reported on bioprosthetic valves, particularly those of porcine origin. The outcome of antifungal
therapy remains poor, with an overall mortality rate of 79%. Special precautions taken for immunocompromised patients may help prevent exposure to fungi during the patients’ period of greatest risk. The development
of newer antifungal agents and combination therapy may hold promise in improving the management of
these devastating infections in the future.
The term “phaeohyphomycosis” was introduced by
Ajello et al. [1] in 1974 to designate infections caused
by dematiaceous or pigmented filamentous fungi that
contain melanin in their cell walls. It literally means
“condition of fungi with dark hyphae.” “Dematiaceous”
has recently come under scrutiny as an improper term
for denoting darkly pigmented fungi, because its root
comes from a Greek word meaning “bundle,” although
the term remains widely used [2]. Phaeohyphomycosis
should be distinguished from other specific pathologic
conditions such as chromoblastomycosis and mycetoma, which are also caused by dematiaceous fungi.
Chromoblastomycosis, which is caused by a small
group of fungi that produce characteristic sclerotic bod-
Received 5 June 2001; revised 19 September 2001; electronically published 9
January 2002.
Reprints or correspondence: Dr. Sanjay G. Revankar, Dallas VA Medical Center,
Div. of Infectious Diseases (111D), 4500 S Lancaster Rd., Dallas, TX 75216
([email protected]).
Clinical Infectious Diseases 2002; 34:467–76
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3404-0007$03.00
ies in tissue, is usually seen in tropical areas [3]. Mycetoma is a deep-tissue infection, usually of the lower
extremities, characterized by the presence of mycotic
granules [3]. Several excellent reviews are available that
discuss these infections caused by dematiaceous fungi
[3–6].
During the past several decades, phaeohyphomycosis
has been attributed to 1100 species and 60 genera of
fungi in a variety of clinical syndromes, ranging from
keratitis and solitary subcutaneous nodules to fulminant, rapidly fatal disseminated disease [5]. Most of the
species are considered to be opportunistic pathogens,
although some may be true pathogens. Almost all cases
of widely disseminated infection have occurred in immunosuppressed patients. We review 72 cases of disseminated phaeohyphomycosis in the literature, including a
case of infection due to Bipolaris spicifera in a heart transplant recipient from one of our institutions. Because
fungal taxonomy is constantly evolving, we have attempted to use the most recent nomenclature available.
We recognize that experts may disagree on particular
taxonomic issues and future changes are likely.
Disseminated Phaeohyphomycosis
• CID 2002:34 (15 February) • 467
Table 1.
Cases of disseminated phaeohyphomycosis reported in the literature.
Patient characteristics
Reference
Year
of
report
Species isolateda
Age in
years,
sex
Risk factor
Site of disease
Therapy
Outcome
Present
report
2001
Bipolaris spicifera
50, M
Cardiac transplant, diabetes
Brain, lung, heart, liver,
spleen, kidney
None
Died
[7]
2001
Alternaria infectoria
60, M
Renal transplant
Lung, skin
Lipid AMB, surgery
Survived
[8]
2001
Scedosporium prolificans
58, F
Multiple myeloma, BMT,
neutropenia
Blood, heart valve
Lipid AMB, Itr, surgery
Died
[9]
2001
Exophiala jeanselmei
18, F
Lymphoma, BMT,
neutropenia
Blood, lung
AMB
Died
[10]
2000
Acrophialophora fusispora
12, F
Leukemia, neutropenia
Brain, lung
Lipid AMB, Itr
Survived
[11]
2000
S. prolificans
45, M
Leukemia, neutropenia
Blood, brain, lung, heart,
liver, spleen, kidney
Lipid AMB
Partial response, died
[12]
2000
Bipolaris species
Premature infantb
Brain, lung, heart, liver,
kidney
Lipid AMB, Itr
Died
[13]
2000
B. spicifera
18, F
None
Lung, lymph node
Itr
Survived
[14]
2000
S. prolificans
77, M
Leukemia, neutropenia
Lung, kidney, skin
AMB, Itr
Died
[15]
1999
Phialemonium curvatum
41, M
Leukemia, neutropenia
Blood, skin biopsy
AMB
Died
[16]
1999
S. prolificans
65, F
Leukemia, neutropenia
Blood, brain, lung, heart,
liver, spleen, kidney
AMB
Died
[17]
1998
Hormonema dematioides
33, M
AIDS
Blood, lung
AMB
Died
[18]
1997
S. prolificans
57, F
Leukemia, BMT,
neutropenia
Blood, brain, multiple
other organs
AMB, G-CSF
Died
S. prolificans
56, M
Leukemia, neutropenia
Blood, lung, multiple
other organs
AMB, Itr
Died
S. prolificans
45, M
Multiple myeloma, BMT,
neutropenia
Blood, brain, multiple
other organs
AMB, G-CSF
Died
S. prolificans
49, M
Leukemia, neutropenia
Brain, lung, multiple
other organs
AMB, Itr, surgery
Died
S. prolificans
27, F
Leukemia, neutropenia
Blood, multiple organs
AMB
Died
S. prolificans
46, F
Leukemia, neutropenia
Blood
AMB
Died
S. prolificans
79, F
Leukemia, neutropenia
Blood
AMB
Died
S. prolificans
55, F
Leukemia, neutropenia
Blood, lung, multiple
other organs
AMB
Died
S. prolificans
67, F
Porcine AVR
Blood
AMB, flu
Died
S. prolificans
43, F
Leukemia, neutropenia
Blood, multiple organs
AMB
Died
S. prolificans
74, F
Leukemia, neutropenia
Blood, skin biopsy
AMB, lipid AMB, Itr, G-CSF
Survived
S. prolificans
52, F
Leukemia, neutropenia
Blood, multiple organs
Flu
Died
S. prolificans
66, M
Leukemia, neutropenia
Blood, brain, kidney, skin
biopsy
AMB
Died
0, F
S. prolificans
48, M
Leukemia, neutropenia
Bone, skin biopsy
AMB, flu, surgery
Survived
[19]
1997
S. prolificans
42, M
Leukemia, neutropenia
Blood, CSF, lung, skin
biopsy
AMB, 5-FC, Flu, G-CSF
Died
[20]
1997
Bipolaris australiensis
21, M
Asthma
Lung, mediastinal mass,
liver
AMB, Itr
Survived
[21]
1997
Scytalidium dimidiatum
44, M
AIDS
Lymph node, skin biopsy
AMB, Ket
Partial response, died
[22]
1996
S. prolificans
60, M
AIDS, lymphoma,
neutropenia
Heart, spleen, kidney
None
Died
[23]
1996
S. prolificans
41, M
Leukemia, neutropenia
Lung, liver, kidney
AMB
Died
[24]
1996
P. curvatum
63, F
Colon carcinoma, porcine
AVR
Blood, heart valve
None
Died
[25]
1996
Curvularia geniculata
10, F
Leukemia, neutropenia
Liver, spleen
AMB, Mic
Partial response, died
[26]
1995
Microascus cirrosus
12, F
Leukemia, BMT,
neutropenia
Lung, skin biopsy
AMB, lipid AMB
Complete response,
died of leukemia
[27]
1995
S. prolificans
32, F
Leukemia, BMT,
neutropenia
Blood, lung
AMB, Itr
Died
[28]
1994
Exophiala castellanii
61, F
Mechanical MVR
Blood, heart valve, psoas
abscess
AMB, Itr, surgery
Survived
[29]
1994
Exophiala mansonii
30, M
Leukemia, neutropenia
CSF, lung
AMB
Survived
[30]
1994
Scopulariopsis brumptii
37, M
Liver transplant
Brain, lung, skin biopsy
AMB, Mic
Died
(continued)
468
Table 1.
(Continued.)
Patient characteristics
Reference
Year
of
report
[31]
1994
S. prolificans
50, F
Lung transplant
Blood, lung, heart, kidney,
spleen
AMB
Died
[32]
1993
S. dimidiatum
13, M
Lymphoma, neutropenia
Blood, skin biopsy
AMB
Survived
[33]
1993
Aureobasidium pullulans
53, F
Ovarian carcinoma, central
venous line
Blood
AMB
Died
[34]
1993
Wangiella dermatitidis
24, M
None
CSF, lymph node, bile
AMB, Flu, 5-FC, Ket, Mic
Partial response, died
[35]
1993
Phialophora richardsiae
52, M
Porcine MVR, diabetes,
steroid use
Blood, heart valve
AMB, surgery
Died
[36]
1993
B. spicifera
24, M
Asthma, steroid use
Lung, adrenal, lymph
node
AMB
Survived
[37]
1993
S. prolificans
17, M
Leukemia, neutropenia
Blood, lung, skin biopsy
AMB, G-CSF
Died
[38]
1993
S. prolificans
72, F
Lymphoma, neutropenia
Blood, CSF, heart, liver,
spleen, muscle
AMB
Died
a
Species isolated
Age in
years,
sex
7, M
Risk factor
Site of disease
Therapy
Outcome
[39]
1992
Myceliophthora thermophila
Leukemia, neutropenia
Heart, lung
AMB
Died
[40]
1992
W. dermatitidis
21, F
CGD
Brain, lung
AMB, 5-FC, Flu, Ket, WBC
transfusion
Survived
[41]
1992
B. spicifera
73, M
Porcine AVR
Blood, heart valve, kidney,
muscle
None
Died
[42]
1992
S. prolificans
Neuroblastoma, BMT,
neutropenia
Blood, lung, skin biopsy
AMB
Died
[43]
1992
3, M
S. prolificans
72, F
Lymphoma, neutropenia
Blood, CSF
AMB, 5-FC
Died
S. prolificans
52, M
Leukemia, neutropenia
Blood, kidney, skin biopsy
AMB, 5-FC
Died
S. prolificans
46, M
Leukemia, neutropenia
Blood
None
Died
S. prolificans
4, M
Aplastic anemia,
neutropenia
Esophagus, liver, spleen
AMB, 5-FC, Flu, Mic, GMCSF
Survived
[44]
1990
Cladophialophora devriesii
26, F
None
Liver, skin biopsy
AMB, 5-FC
Partial response, died
[45]
1990
Ochroconis gallopavum
62, M
Leukemia, diabetes
Brain, lung, liver, spleen,
kidney
None
Died
[46]
1989
Phaeoacremonium parasiticum
92, F
Congestive heart failure
Aorta, hip joint, vertebrae,
skin biopsy
AMB
Died
[47]
1988
E. jeanselmei
50, M
Steroids
Heart, knee joint
AMB
Died
[48]
1988
Fonsecaea pedrosoi
49, M
Renal transplant
Lung, brain
AMB, 5-FC, Ket
Died
[49]
1987
W. dermatitidis
63, M
Bovine AVR
Blood, heart valve
AMB, surgery
Died
[50]
1986
B. spicifera
52, M
Cardiac transplant
Blood, heart, lung, kidney
AMB, Ket
Died
B. spicifera
76, F
Myelodysplastic syndrome
Multiple skin biopsies
AMB
Died
[51]
1986
A. pullulans
28, M
Leukemia, neutropenia
Blood
AMB
Died
[52]
1986
Curvularia lunata
42, M
None
Lung, brain
AMB
Survived
[53]
1985
W. dermatitidis
36, M
Injection drug use
Blood, heart valve, vertebral disc
AMB, Ket
Partial response, died
[54]
1984
Arnium leporinum
19, M
Bioprosthetic AVR and
MVR
Heart valve, kidney, skin
biopsy
AMB
Partial response, died
[55]
1983
Exserohilum rostratum
20, F
Cardiac surgery
Heart valve, vertebrae
AMB, Ket
Survived
[56]
1979
C. lunata
25, M
None
Lung, lymph node, skin
biopsy, muscle
AMB, Mic, surgery
Survived
[57]
1977
Curvularia pallescens
13, M
None
Brain, lung
Mic
Partial response, died
[58]
1973
Lecythophora mutabilis
56, F
Porcine MVR
Heart valve, lung, kidney,
lymph node
None
Died
[59]
1971
C. geniculata
41, M
Asthma, steroid use,
homograft AVR
Brain, heart valve, spleen,
kidney
Surgery
Died
[60]
1966
W. dermatitidis
19, F
None
Brain, lymph node, liver,
pancreas
AMB
Died
c
NOTE. AMB, amphotericin B; AVR, aortic valve replacement; BMT, bone marrow transplant; CGD, chronic granulomatous disease; 5-FC, flucytosine; Flu,
fluconazole; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; Itr, itraconazole; Ket, ketoconazole; Mic,
miconazole; MVR, mitral valve replacement.
a
b
c
See the note to table 2 for the older nomenclature used in the articles.
Twenty-three weeks’ gestation.
Died of recurrent disease [61].
469
METHODS
Literature search. The MEDLINE database (National Library
of Medicine, Bethesda, Maryland) was searched for relevant
articles published during the years of 1966–2001; we looked
for the terms “phaeohyphomycosis,” “disseminated,” and the
genus names for 61 known clinically significant dematiaceous
fungi, primarily from a list compiled by Matsumoto et al. [5].
Additional cases were obtained by scanning the reference sections of the articles obtained via MEDLINE. Only Englishlanguage articles were included.
Definition. Cases were included if all the following criteria
were present: (1) the clinical syndrome was consistent with
infection, (2) recovery of the isolate from blood samples or
evidence of infection at ⭓2 noncontiguous sites, and (3) mycologic identification was confirmed by means of culture.
RESULTS
A total of 72 cases of disseminated phaeohyphomycosis were
studied. These are summarized in table 1. Male patients accounted for 41 (57%) of 72 cases and female patients accounted
for 31 (43%) of 72 cases. The mean patient age was 42 years
(range, 0–92 years). Seventy-five percent of all cases were reported during the years of 1992–2001.
Microbiology. A total of 28 species of fungi were isolated
from the 72 patients with cases (table 2). This list of etiologic
agents is not all-inclusive, nor will it necessarily be agreed upon
by all mycologists or clinicians. The fungi presented here are
those that we think represent the major and adequately documented agents of disseminated phaeohyphomycosis in the
English-language literature. Scedosporium prolificans accounted
for 30 (42%) of 72 cases, by far the most common species
responsible for disseminated disease. Of interest, all of the case
reports involving S. prolificans were published within the past
10 years. The next most common species was B. spicifera, which
was seen in 6 (8%) of 72 patients, followed by Wangiella dermatitidis, which was seen in 5 (7%) of 72 patients. Twenty
species were associated with only 1 case report each, which
illustrates how uncommon many of these infections are. Representative photomicrographs of some of the more common
agents and an example of a Masson-Fontana stain are shown
in figure 1.
Underlying disease and risk factors. Many patients had
11 risk factor (risk factors are detailed in table 3). Some degree
of immune dysfunction was associated with disseminated disease in 55 (76%) of 72 patients. Thirty-nine (54%) of 72 patients had a malignancy diagnosed, and 37 (51%) of 72 patients
had neutropenia, which was most often related to recent chemotherapy. Seven patients were undergoing bone marrow
transplantation, and 6 had received a solid-organ transplant.
Three patients were HIV positive, all of whom had AIDS. Al470 • CID 2002:34 (15 February) • Revankar et al.
most all cases due to S. prolificans (27 [90%] of 30 cases) were
associated with persistent neutropenia. One case was in a premature infant (23 weeks’ gestation).
In 17 (24%) of 72 patients, however, no immunodeficiency
was apparent. Of these patients, previous cardiac surgery had
been performed in 10 (14%) of 69 patients. Nine patients received valve replacements, and all patients but 1 received bioprostheses. There were 5 porcine valve replacements, 1 bovine
valve replacement, 1 homograft, and 1 unspecified bioprosthesis. The mean time from surgery to onset of symptoms was
12 months (range, 2–48 months). A total of 7 (10%) of 72
patients had no apparent risk factor or immunodeficiency. In
some of these patients, immunologic studies suggested a defect
in cell-mediated immunity as measured by T cell stimulation
assays, although the significance of this is unclear.
Clinical characteristics.
Fever was the most common
symptom but was reported in only 55 (76%) of 72 patients.
Skin manifestations, including rash and ulcers, were common
and were seen in 24 (33%) of 72 patients. Respiratory and CNS
complaints were also common, occurring in 22 (31%) of 72
patients. Gastrointestinal symptoms were seen in 12 (17%) of
72 patients. Sepsis was observed in 8 (11%) of 72 patients, 4
of whom were infected with S. prolificans. Marked eosinophilia
was observed in 8 cases of infection. Three of these cases were
due to Bipolaris species, 2 each were due to Curvularia and
Wangiella species, and 1 was due to Lecythophora species. None
of these patients had underlying immunodeficiency, although
1 had been taking steroids for several months.
Sites of infection. The most common site of infection was
blood, which was reported in 37 (51%) of 72 patients. Blood
was the only site of infection in 6 patients. Infection with S.
prolificans was associated with positive blood cultures in 24
(80%) of 30 patients. The next most common site of infection
was lung, seen in 33 (46%) of 72 patients; this was followed
by the heart, in 21 patients (29%); skin in, 19 patients (26%);
brain, in 16 patients (22%); and kidney, in 16 patients (22%).
Liver, spleen, lymph nodes, bone and joints, and muscle were
less commonly reported as sites of infection. The mean number
of organs involved was 3 per patient (range, 1–13 organs per
patient).
Therapy. The most frequently used drug was amphotericin
B, which was administered to 62 (97%) of 64 patients who
received antifungal therapy. Lipid formulations of amphotericin
B were used in only 7 patients, 3 of whom survived. Itraconazole, ketoconazole, fluconazole, and flucytosine were used infrequently. Combination therapy was used in 19 patients: 5
patients received amphotericin B and flucytosine, 10 patients
received amphotericin B and an azole compound, and 4 patients received all 3 agents. In 10 patients, therapy with amphotericin B was followed by therapy with an azole. Recombinant colony-stimulating factors were provided to 5 patients.
Figure 1. a, Scedosporium prolificans (original magnification, ⫻1500). b, Bipolaris spicifera (original magnification, ⫻1500). c, Wangiella dermatitidis
(original magnification, ⫻1500). d, Curvularia lunata (original magnification, ⫻1500). e, Masson-Fontana stain of lung tissue sample obtained from a
patient with disseminated phaeohyphomycosis, demonstrating the characteristic appearance of irregularly swollen hyphae with yeastlike structures
(original magnification, ⫻200).
One patient received leukocyte transfusions. Surgery was performed in 10 patients; usually, the surgery was valve replacement for treatment of fungal endocarditis.
Outcome. The overall mortality was 79% (57 of 72 patients
died). In patients with preexisting immunodeficiency, the mortality rate was 84% (46 of 55 patients died), compared with
immunocompetent patients, for whom the mortality rate was
65% (11 of 17 patients died; P p .09). Recovery from neutro-
penia was considered critical in cases of S. prolificans infection,
for which the mortality rate was essentially 100% in patients
with persistent neutropenia. What is most notable is the lack
of response to amphotericin B in many of the patients: only
14 (23%) of 62 patients who were treated with amphotericin
B survived. Although multiple antifungal agents were often
used, no single drug was associated with improved outcome.
The use of combination therapy did not improve the mortality
Disseminated Phaeohyphomycosis • CID 2002:34 (15 February) • 471
rate: 13 (72%) of 18 patients who received combination therapy
died. Of those treated with amphotericin B and an azole, 11
(79%) of 14 died, although the survival of 1 patient was associated with recovery from neutropenia. The use of recombinant colony-stimulating factors was not associated with improved outcomes, although their use was reported in only 5
patients. All 8 patients who received no antifungal therapy died.
Of these patients, 5 had positive cultures at postmortem examination, and 3 had positive cultures before death that had
not been considered significant at the time.
Geographic distribution. Agents of phaeohyphomycosis
are found worldwide and are predominantly organisms from
the soil. However, the majority of patients were from North
America (23 cases, primarily from the United States) and Europe (28 cases), possibly reflecting a reporting bias. Nine cases
were reported from Australia, 4 cases were reported from the
Middle East, and 4 and 3 cases were reported from South
America and Asia, respectively. Of interest, 24 (80%) of 30
cases of infection with S. prolificans were reported from Spain
or Australia.
DISCUSSION
The number of case reports of disseminated phaeohyphomycosis have been increasing in the past decade. From 1966—the
first case we were able to find described in the English-language
literature—to 1986, there were 11 cases. Eight of the patients
involved had no apparent immunodeficiency. In the past 10
years, 45 cases have been reported, with 41 patients having
some type of immunodeficiency, usually chemotherapy-induced neutropenia. This suggests that the main reason for the
increase in the number of cases of disseminated disease may
be iatrogenic immunodeficiency. Although they are still uncommon as causes of disease, more dematiaceous species are
continually being added to the list of potential fungal pathogens, although many would consider them to be opportunistic
pathogens. Infection may occur when normal barriers are broken (e.g., traumatic inoculation or during surgery), host defenses are weakened by a medical condition or treatment (e.g.,
AIDS- or chemotherapy-induced neutropenia), or in patients
with chronic sinusitis (allergic fungal sinusitis). Occasionally,
certain species of these fungi have been associated with disseminated disease without the above risk factors. Mortality rates
are high regardless of the patient’s immune status.
The common feature among agents of phaeohyphomycosis
is the presence of melanin in their cell walls, which imparts
the characteristic dark color to their conidia and hyphae. It is
thought to play an important role in the pathogenesis of infections due to these fungi. Melanin is a known virulence factor
in fungi and has been extensively studied in Cryptococcus neoformans and Wangiella dermatitidis [62, 63]. Laboratory472 • CID 2002:34 (15 February) • Revankar et al.
Table 2. Agents of phaeohyphomycosis that caused
disseminated infection in humans.
Species
No. of cases
Acrophialophora fusispora
1
Alternaria infectoria
1
Arnium leporinum
1
Aureobasidium pullulans
2
Bipolaris species
1
Bipolaris australiensis
1
Bipolaris spicifera
6
Cladophialophora devriesii1
a
1
Curvularia geniculata
2
Curvularia lunata
2
Curvularia pallescens
1
Exophiala castellanii
1
Exophiala jeanselmei
2
Exophiala mansonii2
1
Exserohilum rostratum3
1
Fonsecaea pedrosoi
1
Hormonema dematioides
1
Lecythophora mutabilis4
1
Microascus cirrosus
1
Myceliophthora thermophila
1
Ochroconis gallopavum5
1
Phaeoacremonium parasiticum6
1
Phialemonium curvatum
2
Phialophora richardsiae
Scedosporium prolificans7
1
30
Scopulariopsis brumptii
1
Scytalidium dimidiatum
2
8
Wangiella dermatitidis
Total
5
72
NOTE. The following are older names used in the articles
for some of the species listed above: 1Cladosporium devriesii,
2
Aureobasidium mansoni, 3Drechslera longistrata, 4Phialophora
mutabilis, 5Dactylaria gallopava, 6Phialophora parasitica, 7Scedosporium inflatum, and 8Exophiala dermatitidis.
a
This was renamed from an isolate identified as Curvularia
boedijn in a report by Shigemori et al. [25]. We were unable to
find such a species on record. On the basis of examination of a
photomicrograph in the article, we suggest the correct identification to be Curvularia geniculata.
derived strains of these fungi that lack melanin demonstrate
markedly reduced virulence in mouse models of infection [62].
There are several mechanisms proposed by which melanin may
act as a virulence factor. It is believed to confer a protective
advantage by scavenging free radicals and hypochlorite that are
produced by phagocytic cells in their oxidative burst, which
would normally kill most organisms [62, 63]. In addition, it
may bind to hydrolytic enzymes, thereby preventing their action
on the plasma membrane [62]. Evidence also exists to suggest
that melanin is involved in formation of the fungal appres-
Table 3.
Underlying disease and risk factors in
cases of disseminated phaeohyphomycosis.
Disease or risk factor
No. of cases
Immunosuppression
46
Neutropenia
37
Bone marrow transplant
7
Steroid use
4
AIDS
3
Aplastic anemia
1
Myelodysplasia
1
Chronic granulomatous disease
1
Malignancy
39
Leukemia
29
Lymphoma
5
Solid tumor
3
Multiple myeloma
Organ transplant
2
6
Heart
2
Lung
1
Liver
1
Kidney
Valve replacement
2
9
Porcine
5
Bovine
1
Homograft
1
Bioprosthesis
1
Mechanical
Other
1
10
Diabetes
3
Asthma
3
Congestive heart failure
1
Cardiac surgery
1
Premature infancy
1
Injection drug use
1
None
7
sorium, a structure involved in pathogenesis that penetrates
host cells [62]. These multiple functions may help explain the
pathogenic potential of dematiaceous fungi, even in immunocompetent hosts.
The diagnosis of phaeohyphomycosis can be difficult to
make, because these fungi are commonly soil inhabitants and
are often considered contaminants when isolated from culture.
As with other filamentous fungi, identification by culture requires expert interpretation of colony and microscopic morphology. No molecular techniques are presently available to
rapidly and reliably identify these fungi to even the genus level.
In tissue, however, they usually have a characteristic appearance
of irregularly swollen or toruloid hyphae with yeastlike structures, in contrast to aspergillosis, which typically shows septate,
acutely branching, straight-walled hyphae [6]. The melaninspecific Masson-Fontana stain has been used to confirm the
presence of dematiaceous hyphae in tissue [6]. However, Kimura and McGinnis [64] reported that other fungi, such as
Aspergillus fumigatus and certain members of the Zygomycetes,
may also stain positive, although less consistently. Culture and
microscopic examination remain the definitive methods to
identify these fungi.
What is particularly unusual about these infections is the
frequent occurrence of positive blood cultures in more than
one-half the cases. S. prolificans is associated with a particularly
high rate of fungemia and was responsible for two-thirds of
positive blood cultures in this series. In contrast, filamentous
fungi, such as Aspergillus species, are rarely isolated from blood
samples, even those obtained from patients with disseminated
disease. The reason for the high rate of fungemia in patients
with disseminated phaeohyphomycosis is unclear, although this
may be a consequence of evasion of host defenses caused by
the presence of melanin. Additional, unknown virulence factors
may also be responsible. In one case of endocarditis due to
Bipolaris species, positive blood culture results were considered
to have been contaminated and no therapy was provided [41].
Although they are frequently contaminants in the laboratory,
agents of phaeohyphomycosis should always be considered seriously when isolated from normally sterile sites in an appropriate clinical setting.
S. prolificans accounted for 140% of cases in this series. It
was first described (as Scedosporium inflatum) by Malloch and
Salkin [65] in 1984, associated with a case of osteomyelitis. It
should be distinguished from S. apiospermum, which has different morphological and physiological characteristics and is
not considered to be truly dematiaceous [66]. S. prolificans also
has a different teleomorph (Petriella species) than S. apiospermum (Pseudallescheria boydii) [67]. In addition, S. prolificans
is generally resistant to all clinically available antifungal agents,
whereas S. apiospermum is susceptible to miconazole and the
newer azoles, including voriconazole and posaconazole [68–71].
S. prolificans was initially reported to cause bone and joint
infections and locally invasive disease in primarily immunocompetent people [43, 72]. Cases of disseminated infection in
immunocompromised, usually neutropenic, patients have become more common [14, 18, 31, 37, 73]. The results of blood
cultures are frequently positive in these cases. Results of antifungal therapy are dismal without recovery from neutropenia,
and mortality rates approach 100%. Of interest, most cases of
disseminated infection have been reported from Spain or Australia. S. prolificans has emerged as an important cause of disseminated phaeohyphomycosis, and more effective therapies
are clearly needed against this opportunistic pathogen.
Many cases were seen in immunocompetent patients. In 8
of 9 cases of endocarditis, bioprostheses were involved, 5 of
Disseminated Phaeohyphomycosis • CID 2002:34 (15 February) • 473
which were porcine in origin. We were able to find 6 additional
cases of prosthetic valve endocarditis, although without positive
blood cultures [74–79]. Four of these were also on bioprosthetic
valves, 2 of which were porcine in origin. It is possible that
either the valves were contaminated or infected before the operation or that contamination occurred during surgery. It has
been suggested that pigs are unusually prone to developing
endocarditis [80]. Approximately 10% of pigs in one large study
had evidence of endocarditis [81]. If the bioprosthetic valves
were not properly sterilized or if the organism was resistant to
the standard sterilization procedure, latent foci of infection
could have been present that manifested clinically when the
valves were implanted in patients. However, given the rarity of
this infection, and given that these fungi are commonly found
in the environment, it is just as likely that contamination occurred during surgery.
In 8 patients, eosinophilia was a prominent feature of the
presentation, and only 1 patient had immunosuppression. Curvularia species and Bipolaris species were responsible for 5 of
these cases. Both agents are important causes of allergic fungal
sinusitis [82, 83], although none of the patients had obvious
sinus involvement. It is unclear what role, if any, the host
allergic response had in the pathogenesis of disseminated disease in these patients. Phaeohyphomycosis should be added to
the list of infections associated with eosinophilia.
In 7 cases, no risk factor was apparent. Three cases were
caused by Curvularia species, 2 were caused by Wangiella species, and 1 each was caused by Bipolaris species and Cladophialophora species. In some of these unusual cases, a variety
of pathogen-specific immune defects have been documented,
although their exact significance in relation to predisposing to
infection remains unclear. It would seem likely that some asyet-undefined defect in natural immunity is present in these
persons that permits the development of widely disseminated
disease.
Current therapeutic options for these devastating and frequently fatal infections are limited. Many isolates of dematiaceous fungi are resistant to amphotericin B, which is often
considered the “gold standard” for empiric and definitive therapy [84]. Among available agents, itraconazole has the most
consistent and potent activity, and an intravenous formulation
has recently become available [84, 85]. Terbinafine, although
primarily indicated for management of dermatophyte infections and onychomycosis, has been shown to have significant
in vitro activity against dematiaceous fungi [86]. There are case
reports of successful treatment of cutaneous phaeohyphomycosis with terbinafine as well [87, 88]. Some of the many new
antifungal agents being developed hold promise for improving
the therapy of these infections in the future. Voriconazole, posaconazole, and ravuconazole are potent new azole derivatives
with a generally broad spectrum of activity against dematia474 • CID 2002:34 (15 February) • Revankar et al.
ceous fungi [68, 69, 89, 90]. Caspofungin, a recently approved
echinocandin antifungal, acts on the fungal cell wall by inhibiting glucan synthase. It does not appear to be as active in vitro,
as the azole compounds are, and its role in treating these infections is unclear at present [70].
Combination therapy is another option, although there is
limited clinical experience. On the basis of the cases reviewed
here, amphotericin B combined with azoles does not appear
to improve the outcome of cases of disseminated phaeohyphomycosis. For species such as S. prolificans, no currently
approved systemic antifungal agent has significant activity, although voriconazole, an investigational triazole, may have some
activity [71]. However, there is promising in vitro data suggesting that the combination of itraconazole and terbinafine is
synergistic against S. prolificans [91]. This may be a useful strategy, because both drugs act at different levels of the ergosterol
synthetic pathway. Overall clinical experience will ultimately
determine which agent or combination of agents is most effective, because it is unlikely that formal clinical trials will be
performed, given the rarity of these infections.
Preventive measures may be important to reduce the incidence of these and other mold infections in immunocompromised patients in the future. Given the poor outcome of
therapy in patients with immunodeficiency, chemoprophylaxis
may be of additional benefit in those persons at highest risk,
although this has not been specifically studied with agents of
phaeohyphomycosis. Many solid-organ and bone marrow
transplant recipients already receive antifungal prophylaxis for
Aspergillus species with itraconazole, which has activity against
dematiaceous fungi. Because many of the agents of phaeohyphomycosis are common soil inhabitants, they are ubiquitous
and difficult to exclude from the hospital environment. Although they have not been studied specifically for prevention
of phaeohyphomycoses, air-quality precautions (e.g., positivepressure isolation rooms and high-efficiency particulate air filters) used to control aspergillosis in some solid-organ and bone
marrow transplant units may help control the surroundings of
severely immunocompromised patients in the hospital [92].
Disseminated phaeohyphomycosis is an uncommon infection, although its incidence may be increasing, particularly in
immunocompromised patients. Aggressive diagnosis and careful interpretation of culture results are important for the treatment of these patients. Newer antifungal agents and therapeutic
options will be needed in the future to improve the outcome
of these frequently fatal infections.
Acknowledgments
We thank Dr. Joseph McCormack and Dr. Marcio Nucci for
providing information regarding the clinical cases.
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