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Weird Fungi
Overall, more than 270 fungal species, some only weakly virulent, may
produce disease in humans, particularly the immunocompromised
John R. Perfect
n the last decade, clinical practice has
seen a boom in technology and therapeutic maneuvers to manage serious lifethreatening diseases. A consequence of
this medical progress has been the frequent appearance of opportunistic infections
among immunocompromised patients. This
trend has been particularly noticeable in the
appearance of medical mycoses. A common comment by clinicians in medical centers caring for
severely immunosuppressed patients is “that is a
weird fungus; is it causing disease?” There are no
taxonomic terms for “weird fungi” or a specific
species designation, but the axiom “you know
them when you see them” usually applies. The
definitions of weird include “of fate or destiny”;
“suggestive of ghosts, evil spirits, unearthly, mysterious”; and “strikingly odd, strange, queer, bizarre.”
These three definitions correspond to concepts that can be used to categorize these fungi
in modern medicine. Beyond these terms, weird
I
• Even though some pathogenic fungi remain unfamiliar and appear “weird,” the basic principles
of accurate diagnosis and creative treatment strategies still apply.
• Immunocompromised individuals risk infections by more than 270 fungal species, with some
only weakly virulent, and clinical outcome often
reflects the seriousness of a patient’s underlying
disease.
• Foreign materials often foster fungal infections,
and creative strategies may be needed to manage
such infections, including the use of antiseptic
solutions to treat topical infections or reconstituting immune responses to deal with recalcitrant
internal infections.
also embodies a useful mnemonic for clinicians
and clinical microbiologists to keep in mind
when confronting difficult cases:
What is the epidemiology?
Establish infection
Invite experts to review these cases early
Respond to infection with a plan
Don’t ever give up with these infections unless
underlying disease makes you.
Even though such fungi tend to be viewed with too
much awe because they are so unfamiliar, the basic
principles of accurate diagnosis and creative treatment strategies still apply when it comes to managing complicated cases.
Weird in Terms of Fate or Destiny
First, it is important to emphasize that “weird
fungi” may have institutional and geographical
differences in their appearance. For instance,
one medical center has described an impressive
number of positive cultures for Fusarium
species from a variety of environmental water sources. This environmental water contamination eventually led to cases of invasive fusariosis in neutropenic patients. In
fact, with the use of molecular genotyping
these environmental mould strains have
been directly linked to clinical disease.
However, it is important to emphasize that
these fungi will not occur at the same frequency in all medical centers. Epidemiological differences between medical centers occur simply because environmental water
contamination varies between institutions,
and the risk population of patients may be
significantly different.
Second, persistently immunosuppressed
patients cannot live in sterile environments.
John R. Perfect is a
Professor of Medicine in the Division
of Infectious Diseases, Department
of Medicine, Duke
University Medical
Center, Durham,
N.C.
Volume 71, Number 9, 2005 / ASM News Y 407
FIGURE 1
infection and even death. Therefore, the
host frequently controls the destiny or
fate of infection with these fungi.
Finally, there is simply a lack of evidence-based studies for management of
these “weird fungi.” The numbers of
cases for each fungal species are simply
too few, or cases are too complex, to
allow any robust general statements
about treatment strategies. Clinicians
will frequently learn about management strategies one case at a time.
Weird in Terms of of Ghosts, Evil
Spirits, Unearthly, Mysterious
Since many of these “weird fungi” are
saprobes which might colonize nonsterile body sites or even contaminate cultures, it is important to have histological confirmation of infection and a
positive culture from a sterile body site
to document an etiologic agent for disease. For example, the histological appearance of uniform, septated hyphae
A mixture of unicellular and multicellular elements caused uncertainty in the histologic
diagnosis of Phialophora richardsiae subcutaneous infection, until culture results became
in tissue could represent several moulds
available. GMS stain, cutaneous biopsy.
such as Aspergillus, Fusarium, or Scedosporium species, making culture
identification helpful in clarifying what
mysterious fungus is producing disease.
It is more common for clinicians to manage
On the other hand, frequently ribbon-shaped,
these severely immunocompromised cases as
nonseptated hyphae are detected in tissue with
outpatients, who will be more frequently exZygomycetes infections while subsequent tissue
posed to some of the over 270 fungal species in
cultures are negative. Thus, tissue histopatholthe environment known to produce human disogy is the primary mode of identification. Some
ease. This environmental exposure can reach
moulds, such as Fusarium spp., Paecilomyces
from the barnyard to the hospital, and a variety
lilacinus, Scedosporium prolificans, Aspergillus
of weakly virulent fungal strains produce infecterreus, and some of the black moulds, may
tion in immunocompromised hosts. Furtherappear as both yeast and hyphae in tissue, as
more, in many cases of disease with these “weird
they produce adventitial forms at the site of
fungi,” the clinical outcome does not necessarily
infection. A solid organ transplant recipient develcorrelate with the virulence of the strain or its
oped an infection with Phialophora richardsiae
appearance of drug resistance, but its damage to
that led to a cystic lesion on one hand, vividly
the host simply reflects how advanced the underdemonstrating the weird morphology that some of
lying disease of the patient may be.
these fungi can produce (Fig. 1).
For example, Shahid Husain and colleagues at
Accurate mycological identifications of
the University of Pittsburgh, Pittsburgh, Pa.,
“weird fungi” are essential. For instance, a
studied the outcome of solid organ transplant
bronchoalveolar lavage (BAL) fluid with Penirecipients with mould infections. The survival of
cillium species growing in it raises vastly differpatients infected with fungal species was the
ent clinical concerns compared to BAL fluid
opposite of what one would predict from direct
with Dactylaria gallopava. The first fungus is
virulence studies of the fungal pathogens in anlikely an airway colonizer, and the second
imals, illustrating that the weakest host fremould may be producing disease. In fact, except
quently allows the “weirdest” fungus to cause
408 Y ASM News / Volume 71, Number 9, 2005
for Penicillium marneffei, there are very
FIGURE 2
few cases in which Penicillium species
have caused disease, despite their frequent isolation in nonsterile clinical specimens. On the other hand, the uncommon isolation of a Dactylaria species
from a clinical specimen and its known
virulence potential both in animals and
humans make it a much more likely
pathogen. While there are clinical circumstances in which obtaining histopathology and culture from a sterile body
site is simply not possible, such as in the
case of a severely neutropenic/thrombocytopenic cancer patient, there is simply
no substitute for accurate clinical mycology in patients that are immunocompromised and require antifungal management.
Mysteriously, weird fungi will occasionally contribute to an outbreak of
multiple infections. For example, four
cases of Phialemonium infection leading
to two deaths occurred in patients undergoing chronic hemodialysis. Another outbreak of Phialemonium curvatum was
associated with contaminated injectable
drugs. In an impotence clinic, a vasoactive cocktail of drugs was used for intraLeft panels: Skin lesions caused by Rhizomucor sps. on arm before therapy. Top and
cavernous penile injection for impotence.
middle right panels: Rhizomucor skin lesions after 5 days of ABLC treatment. Bottom
Three patients using these self-adminisright panel: New skin lesion on arm caused by Aspergillus flavus at 7 days of ABLC
treatment.
tered injections developed endocarditis
with this weird fungus, which was later
directly recovered from the drug vials.
Similarly, five cases of Wangiella dermatitidis
must be under strict sterility control or weird
meningitis resulted from contaminated injectable
fungi may infect patients. Care must also be
steroids for back pain. Two of these patients died,
taken to ensure that invasive technology is sterbut three received an extended treatment course
ile. For instance, even mushrooms will grow on
with voriconazole, and their infections were sucvascular stents within the human body. Another
cessfully managed.
example of direct fungal implantation is fungal
There are several properties of weird fungal
keratitis either through contact lenses, LASIX
infections to keep in mind. First, as in those
surgery, or corneal transplants. The cornea,
three outbreaks, most “weird fungi” need help
with its reduced vascular supply and with the
to produce infection. They can grow at body
frequent use of corticosteroid drops for corneal
temperatures, but many species poorly adapt to
eye disease, has become a common site of infecthe harsh host environment. However, foreign
tion with “weird fungi.” Finally, some soft tisbodies from insertion of catheters and stents to
sue infections with weird fungi exhibit few
trauma from wood twigs and other inanimate
symptoms in the patients for months or years,
objects are common modes of introducing these
making it difficult to identify the environmental
fungi into the bloodstream, skin, or soft tissue of
source for them.
an immunocompromised host. As cases involvIn the management of infections with “weird
ing contaminated drugs demonstrate, the profungi,” identification to a species level can also
cessing and dispensing of injectable material
be helpful to clinicians when choosing antifun-
Volume 71, Number 9, 2005 / ASM News Y 409
Key Concepts Regarding Weird Fungi
• Fungi may travel by weird routes to sites where they cause infection,
including by contaminated skin lotions, twigs, catheters, stents, injectable medications, and even oral medications and nutritional supplements
• Fungi may use peculiar routes to gain access to unexpected sites in the
body; for instance, fungi such as Acremonium strictum, Trichoderma
longibrachiatum, and Mucor indicus can enter through the gastrointestinal tract
• Some odd behaviors of infectious fungi elude ready explanation
• Many times weird fungi produce more fright than bite (see table); for
instance, Trichosporon beigelii in urine typically is benign and a sign of
a contaminated catheter, but in neutropenic patients it might indicate
disseminated disease
Weird fungi that produce infections in humansa
Species that Produce Infections at Relatively Greater Frequencies
Acremomium spp.
Lasiodilodia theobromae
Alternaria alternate
Malassezia furfur
Apophysomyces elegans
Paecilomyces lilacinus
Aspergillus terreus
Paecilomyces variotii
Bipolaris spp.
Penicillium marneffei
Bipolaris spicifera
Phialemonium curvatum
Blastoschizomyces capitatus
Phialophora parasitica
Candida krusei
Phialophora richardsiae
Candida lusitaniae
Ramichloridium spp.
Cladophialophora bantiana
Rhizomucor pusillus
Cunninghamella bertholletiae
Rhizopus rhizopodiformis
Curvularia lunata
Rhodotorula rubra
Exserohilum rostratum
Saccharomyces cerevisiae
Fusarium moniliforme
Scedosporium prolificans
Fusarium solani
Trichosporon beigelii (T. asahii)
Hansenula anomala
Wangiella dermatitidis
Species that Produce Infections at Relatively Lower Frequencies
Absidia corymbifera
Hormonema dematioides
Acremonium strictum
Lecythophora hoffmannii
Aspergillus nidulellus
Lecythophora mutabilis
Aureobasidium pullulans
Nodulisporium spp.
Botryomyces caespitosus
Penicillium spp.
Candida zeylanoides
Phialemonium dimorphosporum
Chaetomium globosum
Phialemonium obovatum
Chrysosporsium parvum
Phoma spp.
Conidiobolus coronatus
Pseudomicrodochium spp.
Conidiobolus incongruus
Rhinocladiella spp.
Dactylaria constrica var. gallopava
Saksenaea vasiformis
Exophiala moniliae
Schizophyllum commune
Exophiala spinifera
Scopulariopsis spp.
Fusarium chlamydosporum
Scytalidum spp.
a
From Perfect and Schell, Clin. Infect. Dis. 22:112–118, 1996.
410 Y ASM News / Volume 71, Number 9, 2005
gal treatments. For example, Paecilomyces
variotii is generally very susceptible to standard antifungals, but Paecilomyces lilacinus
can be resistant. Similarly, Scedosporium
apiospermum responds to treatment with
drugs such as voriconazole and possibly
caspofungin, but Scedosporium prolificans
is intrinsically resistant to available antifungal agents. Although not specifically predictive of clinical outcome, in vitro mould susceptibility testing with the NCCLS M38A
method can indicate whether a strain may be
clinically susceptible to a specific drug. Ultimately, “weird fungi” may require creative
treatment strategies such as a combination of
systemic drugs or even the use of antiseptic
solutions for topical administration at the site
of infection (e.g., soft tissue; cornea) along
with surgical debridement.
Weird in Terms of Strikingly Odd,
Strange, Queer, Bizarre
Although the majority of cases with invasive
“weird fungi” occur in immunosuppressed
patients, not all of them do. For instance,
brain abscesses with Cladophialophora
bantianum or Ramichloridium species may
strikingly appear in apparently normal individuals. The “weird fungus” on the cover of
this issue was cultured from a traumatic soft
tissue infection in an apparently normal 15year-old female.
Fungi such as Paecilomyces species can
strangely produce infection by contaminating lotions used on the skin of bone marrow
transplant recipients. Bizarrely, papular
skin lesions may appear in immunocompromised hosts that, upon biopsy, show yeast
even though cultures are negative. In such
cases, clinicians must consider Malassezia
species as a cause since these fungi need
extra lipids to grow in commonly used clinical media.
In some severely immunosuppressed patients, “weird fungi” can illustrate how
some patients have become “human Petri
dishes.” For instance, more than one fungal
pathogen can cause infection at the same
time in the same patient, making it necessary to biopsy two different skin lesions for
histopathology and culture. Detection of
more than one fungus might even lead to a
change in management strategy, since we now
have several different systemic antifungal drugs
to use. In one case, a farmer with myelofibrosis
progressing to leukemia developed several lesions on his arm after working in his garden
(Fig. 2). These skin lesions were caused by Rhizomucor species. As therapy with amphotericin
B lipid complex (ABLC) started to help heal
these lesions, a new lesion started to grow on the
arm that was caused by Aspergillus flavus. The
treatment was changed to posaconazole, after
which all skin lesions cleared.
In considering individual cases of weird fungi,
several important clinical issues stand out. First,
there is no substitute for a correct diagnosis, and
it may require both histopathology and culture
confirmation. Second, reconstituting immune
function may be essential to clear an established
infection with a weird fungus, even when the in-
fection is treated with very active antifungal
agents. Third, in some cases, the burden of weird
fungi may be so high that no antifungal therapy or
immune reconstitution can control the infection.
Finally, some of these weird fungi have caused
so few reported cases of disease and are so
refractory to standard treatments that a multilayer approach may be necessary for successful
management. Infections with weird fungi at times
need to be treated with weird therapeutic regimens. These regimens may entail combining topical and systemic antifungal agents (azoles, flucytosine, polyenes, candins, and allylamines), possibly
with surgery and occasionally with immunomodulation therapy, such as gamma interferon
and colony stimulating factors. The important
feature for the final cure of these infections is
frequently to correct or control the underlying
disease and/or decrease immunosuppression.
ACKNOWLEDGMENT
The figures on fungal morphology, including the cover, were supplied by Wiley Schell from his photographic collection.
SUGGESTED READING
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Volume 71, Number 9, 2005 / ASM News Y 411