Download Cutaneous infections due to opportunistic molds

Clinics in Dermatology (2005) 23, 565 – 571
Cutaneous infections due to opportunistic molds:
uncommon presentations
Irina Vennewald*, Uwe Wollina, MD
Institute of Laboratory Medicine, Academic Teaching Hospital Dresden-Friedrichstadt, 01067 Dresden, Germany
Department of Dermatology, Academic Teaching Hospital Dresden-Friedrichstadt, 01067 Dresden, Germany
Abstract Molds are quite more often suspected as pathogens by the public than by the medical care
community. Molds may, however, cause serious medical problems, and mold infections can develop
incognito. Among the mycoses caused by opportunistic molds, alternariosis and fusariosis together with
aspergillosis are of particular importance. They are more common than other groups with pathological
characteristics. The aim of our presentation is to demonstrate the important role of common molds as
causative agents in skin and ear infections. The clinical picture, etiology and pathogenesis, diagnosis
and treatment, and course and prognosis of cutaneous infections will be given. The spectrum of clinical
symptoms ranges from eczemalike lesions to chronic erythematous, verrucous lesions of the skin or
multiple acute infiltrations of the dermis, occasionally forming abscesses. The mycologic direct
preparation of the specimens, particularly with optical brighteners, and a histological examination of a
skin biopsy are strongly recommended. The outbreak of cutaneous infections is triggered by weakened
host defense mechanisms. A review of the literature regarding immunosuppressed and immunocompetent patients will be given.
D 2005 Elsevier Inc. All rights reserved.
Introduction
The problem of pathogenicity of molds in dermatology
has been known for some time. Whenever molds are found
on the skin, the question arises as to whether they represent
a contamination, a saprophytic colonization, or a clinically
relevant infection. The mycologic direct preparation of the
specimens, particularly with optical brighteners, signifi-
T Corresponding author. Mykologisches Labor, Institut fqr Klinische
Chemie und Labormedizin, Akademisches Lehrkrankenhaus DresdenFriedrichstadt, 01067 Dresden, Germany. Tel.: +49 351 480 3861; fax: +49
351 480 3236.
E-mail address: [email protected] (I. Vennewald).
0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2005.01.003
cantly improves the immediate diagnosis of dermatomycosis.1,2 Histological examination of a skin biopsy is strongly
recommended. The complete review Atlas of Clinical
Fungi 3 and other very informative references offer great
support for diagnosis and risk assessment of fungi.4- 6
The aim of our presentation is to demonstrate the important
role of common molds as causative agents in skin and
ear infections.
Among the mycoses caused by opportunistic molds,
alternariosis and fusariosis are of particular importance.
They are more common than other groups with pathological
characteristics. In addition, they show many unusual traits.
These two groups of mycosis are described in detail in the
following sections.
566
I. Vennewald, U. Wollina
Alternariosis
Definition
Alternariosis is a form of phaeohyphomycosis caused by
cosmopolitan opportunistic molds of the genus Alternaria.
Causative organism (fungi) and epidemiology
The organism lives in soil, on organic detritus, and as
saprophytes and parasites of various plants. Only six species
are described as human pathogens in the Atlas of Clinical
Fungi: Alternaria alternata, A chlamydospora, A dianthicola, A infectoria, A tenuissima, and A longipes. The
infections are not contagious.
Etiology and pathogenesis
A main predisposing factor of alternariosis is hypercorticism, which may be endogenous (Cushing disease) or
therapeutically induced.
Three forms of alternariosis can be distinguished:
1.
2.
3.
exogenous, superficial form caused dermatopathy;
exogenous, unilocular form of traumatic origin;
endogenous, multilocular, disseminated form.
Clinical manifestation
The spectrum of clinical symptoms ranges from localized
epidermal eczemalike lesions to extremely chronic solitary
verrucous lesions of the skin to multiple acute infiltrations
of the dermis, which occasionally form abscesses.7
Exogenous, superficial form caused by dermatopathy
Clinical symptoms result from seborrheic eczemalike
alteration of the skin, particularly after treatment with
steroids or antibiotics. The skin shows erythema and
desquamation or red papules with a granular surface, which
are usually painless. In particular, erosion and ulceration can
develop after treatment with corticosteroids. The localization is mostly paranasal and on the cheeks.7-9
Histological examination of the skin biopsy shows
hyperkeratosis, parakeratosis, and fungal elements in the
epidermis. With progressive-type disease, microabcesses
with fungal hyphae may be observed.
Exogenous, unilocular form of traumatic origin
This form of infection is associated with a penetrating
injury by a foreign body or trauma. The infection follows a
traumatic introduction of the fungus into the skin, such as by
cuts or wounds caused by thorns or wood splinters. This
form is found in healthy patients. The skin lesion appears as
a livid-red plaque with superficial central ulceration.
Without adequate treatment, this kind of plaque can develop
into a crust-ulcerous lesion of remarkable size.7,10 -14
The outbreak of mycosis can be as late as 10 to 40 years
after the initial inoculation and might be triggered by a
weakening of host defense mechanisms.
The skin lesions are found on bare parts of body, legs, and
arms. Usually, patients who work outdoors such as farmers,
gardeners, and car drivers are affected. This relationship
with outdoor profession cannot be seen in the other forms
of alternariosis.
Histological examination of the skin biopsies of these
patients reveals epidermal acantholysis and parakeratosis. A
subepidermal abscess contains neutrophils. The corium
shows granulation tissue (granuloma) containing histiocytes, plasma cells, and giant cells of foreign-body types.
After periodic acid–Schiff and Grocott-Gömöri methenamine-silver stains, septate hyphae can be found within the
granuloma, microabscesses, and giant cells.
Endogenous, multilocular form
This form most probably originates from metastatic
invasion of disseminated alternariosis.7,14 -22 Underlying
conditions may be the following:
1.
2.
3.
hypercorticism caused by Cushing disease;
neutropenia as a result of a malignant condition;
organ transplantation and its treatment.
The entry of Alternaria species can be paranasal
sinusitis, pneumonia, or wound infection after surgery.
Outbreak or significant worsening of alternariosis has
been described after corticosteroid therapy. In addition,
most of these patients suffer from steroid-induced diabetes mellitus.
Skin manifestations appear with multiple erythematous
and partially necrotic papules approximately 1 cm in
diameter. Papulonodular lesions approximately 3 to 4 cm
in diameter or cutaneous nodules can also be observed. These
manifestations are usually painless.14,17,18,20 In general, the
patients are in otherwise good condition, afebrile, and have
no other signs of infection. The lesions are often found
simultaneously on the trunk, neck, and limbs.
Histological examination of a skin biopsy reveals an
epidermis of normal conformation and various dermal
granulomas, as well as an occasionally occurring central
abscess. Mixed infiltrates consisting of macrophages,
plasma cells, and neutrophils can be seen. No foreign body
reaction is observed. Special stains for fungi, periodic acid–
Schiff and Grocott-Gfmfri methenamine-silver, show occasional septate hyphae and many round bodies in the
granuloma center.15 -19
The skin lesions of patients with bone marrow aplasia
may reveal a dense dermal infiltration by septate hyphae
without inflammation. Macroconidia of Alternaria, single or
in short chains, are occasionally present.20
Diagnosis
Laboratory diagnosis includes direct microscopy, culture,
and, in selected cases, histopathology. Diagnosis is usually
obtained by skin biopsy, a sterile skin needle puncture, or
swabs from skin lesions, wound fluids, or ulcers.
Cutaneous infections due to opportunistic molds: uncommon presentations
Mycology
Direct microscopic examination after 15% to 30% KOH
preparation of skin samples shows numerous dark brown
septate hyphae, partially branched and sometimes few
Alternaria conidia.
Skin samples are cultured on Sabouraud glucose agar
with and without cycloheximide at room temperature and
378C. After 3 days of incubation, the culture of the skin
samples forms white-brown mold colonies. No growth can
be observed on cycloheximide-containing media. Morphological identification is obtained on malt agar within 48
hours. Very good growth and production of typical brown
conidia in chains can be found at 308C to 338C.
Course and prognosis
Usually, the course of alternariosis is asymptomatic.
Often, the patients do not realize the skin lesions because
they are painless and without pruritus. The course of disease
lasts many weeks or months. The prognosis is good.
Spontaneous remissions of patients with dermatopathic
form have been published when the underlying condition
improves and steroid therapy can be stopped. Fungal spread
from primary cutaneous lesions has not been described.
2.
3.
567
a unilocular form of exogenous traumatic origin25,26;
an endogenous multilocular form that most probably
originates from metastatic invasion of disseminated
fusariosis.27-38
The port of entry for Fusarium infection is unclear. The
fungus may enter through skin lesions. A toenail lesion has
been suspected as the port of entry by several
authors.23,24,33,37,38 Onyxes due to Fusarium are not
uncommon, in particular, in patients who underwent
chemotherapy or bone marrow transplantation. Airborne
infection is also possible, as Fusarium was isolated from
bronchoalveolar lavage fluid or sputum. Sinusitis can be a
starting point for infection.
The following diseases can be associated with Fusarium
infections: burns, diabetes mellitus, cancer, or AIDS.
Patients who underwent bone marrow transplantation are
most susceptible to Fusarium infection. Fusarium is the
second most frequent fungal agent after Aspergillus.37
Corticosteroid therapy is not a risk factor for Fusarium
infections. Prolonged aplasia and pancytopenia increase the
risk of Fusarium infection. Skin (60-80%) and blood (4050%) are the sites most frequently involved.30,37,38
Clinical manifestations
Treatment
Surgical excision is the method of choice. If the excision
is not complete, a relapse will occur after a short remission.
In some cases, cure has resulted from debridement
combined with antifungal therapy. Alternaria species are
susceptible to antifungal drugs such as ketoconazole,
itraconazole, voriconazole, and sertaconazole.
Superficial form
The patients are usually in good general health and
develop skin lesions attributed to Fusarium species despite
the lack of clinical evidence of a systemic immunodeficient
state or a skin damage.
1.
Fusariosis
Definition
Fusariosis is a form of hyalohyphomycosis caused by
cosmopolitan opportunistic molds of the genus Fusarium.
Causative organism (fungi) and epidemiology
Fusarium species are opportunistic molds and are present
in soil and on plants. Only 13 species are known to be human
pathogens; those most often isolated from the cutaneous
lesions are Fusarium solani, F oxysporum, F verticillioides,
and F proliferatum. The infections are not contagious.
Etiology and pathogenesis
The fusariosis can be devised into three forms:
1.
a superficial form of patients with good health
status23,24;
a. interdigital intertrigo,
b. paronychia.
2.
Interdigital intertrigo of the feet. Sometimes intertrigo is associated with alteration of the toenails.
Some patients complain about focal hyperhidrosis.23
The patients have normal immune status and a
history of infection extending several years. The
patients often went barefoot. The affected skin is
macerated, eroded, and painful.
Paronychia of fingers shows acute and pustulous
lesions, erythema with dry desquamation, or erythema with onychomycosis. The lesions are painful and
have a history of 5 to 12 months. Housewives seem
to be the special risk group.24
Often, patients are initially treated with topical corticosteroids, which cause the clinical symptoms to become
worse.
Histological examination of biopsy fragments stained
with hematoxylin-eosin shows hyperkeratosis, zonal parakeratosis, slight spongiosis, and epidermal acanthosis. In the
superficial dermis, perivascular lymphohistiocytic infiltration with occasional eosinophilic granulocytes can be seen.
In the stratum corneum, numerous septate hyphae or spores
are found with periodic acid–Schiff staining and GrocottGömöri methenamine-silver staining.
568
Exogenous, unilocular form of traumatic origin
This form may take an acute or chronic course of
fusariosis in patients of normal health status. The acute
infection develops a few weeks after an injury caused a
foreign body (thorns, fish barb, or wood splinters). Despite
surgical and antibiotic treatment, an erythematous lesion of
4-cm diameter with progressive induration develops around
the wound. Straw-colored fluid is discharged. After
minimal covered trauma, chronic infection can develop as
long as 1 year later. The skin shows abscess formation with
fluctuation. Predominant localization of such a lesion is on
bare limbs.25,26
Histological studies show fibrous tissues with ill-defined
granulomatous inflammation (granuloma with central
necrosis). Elongated and septate hyphae can be found in
the lesion.
I. Vennewald, U. Wollina
Fusarium infection in immunosuppressed patients can
develop into an acute invasive form with lethal consequences when not treated properly with systemic antifungal drugs.
Retrospective studies confirm that Fusarium infection
mainly affects severely immunosuppressed patients such as
those with hematologic malignancy.31,37,38 The prognosis in
similar groups of patients is clearly better than that for
invasive aspergillosis. This suggests of a lower pathogenicity of Fusarium. Because the prognosis is closely correlated
with neutrophil recovery, promising therapeutic results
obtained with the use of colony-stimulating factors should
be further evaluated.
Treatment
Cure can be achieved by surgical excision with debridement and skin grafting in conjunction with antifungal drugs.
Fusarium species are susceptible to amphotericin B,
voriconazole, sertoconazole, and terbinafine.
Endogenous, multilocular form, probably originates
from metastatic invasion of disseminated fusariosis
Painful erythematous maculae or papules with progressive central infarction occur surrounded by an erythema. The
lesions are often found simultaneously on the trunk, face,
limbs, balls of the toes, or on the finger pad.27,30 -35,38 In skin
biopsies, fungal hyphae are seen predominantly in capillaries
and small vessels, infiltrating surrounding tissue structures
and causing edema, epidermolysis, and focal necrosis.
Sometimes, fungal hyphae are present in the connective
tissue without an inflammatory reaction.30,33 -35,38
The term otomycosis is used to describe mold or yeast
infections of the external auditory canal.
Diagnosis
Causative organism (fungi) and epidemiology
Laboratory diagnosis includes direct microscopy, culture,
and, in selected cases, histopathology.
Molds and yeasts are common in the auditory canals of
healthy people, but the percentage of isolated Aspergillus
and Candida species is very low.39 Many authors have
reported only Aspergillus isolates of patients with otomycosis.40 - 48,50 The predominance of thermophile Aspergillus
and Candida species is related to the inflammatory processes of the ear. Etiologic agents causing fungal infection
in the ear were reported to be in two thirds of cases molds
and in one third yeasts.51
The molds mostly isolated from the ear are listed in
Table 1.40,41,49 -52 The Aspergillus species represent 95% of
the molds isolates with a predominance of Aspergillus
niger, followed by Aspergillus fumigatus and Aspergillus
flavus. The infections are not contagious.
Mycology
Direct microscopic, mycologic examination of skin
fragments, macerated in 15% to 30% KOH, reveals hyaline
septate hyphae of irregular diameters, which are sometimes
contorted and much larger than those of dermatophytes.
Skin samples are cultured on Sabouraud glucose agar
with and without cycloheximide at room temperature and
378C. After 3 to 5 days of incubation, the culture of the skin
samples forms pink, yellow, or purple mold colonies. No
growth can be observed on cycloheximide-containing
media. Morphological identification can be obtained on
malt and oatmeal agar within 1 week.
Microscopic examination shows that the colonies consist
mainly of sickle-shaped macroconidia. Chlamydospores
were mostly observed in older cultures after exposure to
daylight. The Fusarium colonies need the day-night rhythm
for the building of fruiting bodies.
Course and prognosis
The prognosis of immunocompetent patients is good,
although with topical treatment, the course of disease lasts
many weeks or months.
Otomycosis
Definition
Table 1 Spectrum of molds isolated from the external and
middle ear
Aspergillus
Aspergillus
Aspergillus
Aspergillus
Aspergillus
Aspergillus
Aspergillus
niger
fumigatus
flavus
terreus
candidus
hollandicus
alliaceus
Aspergillus janus
Aspergillus versicolor
Aspergillus nidulans
Paecilomyces variotii
Mucor species
Penicillium species
Cutaneous infections due to opportunistic molds: uncommon presentations
Etiology and pathogenesis
Whenever fungi are found in the ear, the question arises
whether they represent colonization or clinically relevant
infection.
Persisting discharge with maceration of the meatal
epithelium may support fungal colonization of the external
ear in patients with otitis media. The demonstration of
conidiophores (Aspergillus heads) in the auditory canal is
consistent with the hypothesis that mucous discharge serves
as a nutrient. Clinically relevant infections are accompanied
by inflammation.51
The reason for this discharge lies in the chronic
hyperplastic inflammation of the mucous membrane in the
middle ear. This results in a disturbance of the continuous
drainage of fluids from the middle ear cavity to the auditory
tube, perforation of the tympanic membrane, and relapsing
otorrhea. The persisting tympanum perforation is an entrance
to the middle ear. A primary infection may arise from the
oropharynx via the auditory tube. Infection by molds, in
contrast to bacteria and yeasts, is only possible after
perforation of the eardrum.51,53
Clinical manifestation
Fungal infection of the ear occurs in three primary types:
(1) chronic colonization, (2) acute invasive, and (3) chronic
invasive. The patients can be classified by their clinical
history into two groups:
1.
The larger otomycosis group is represented by patients with chronic otitis media and persisting
perforation of the tympanic membrane with otorrhea
with or without cholesteatoma. Most of these patients
(86%) are not neutropenic or otherwise immunocompromised and have been experiencing chronic
otitis media for many years. These patients had longterm relapsing otorrhea and had been treated repeatedly with antibiotics without achieving remissions.
They show chronic fungal colonization of the
auditory canal.51
Usually, the patients complain about the following
symptoms:
!
!
!
!
persisting white or colorless otorrhea with tympanum
perforation;
edema, erythema of tympanic membrane residuum,
ear pain, pruritus;
whitish, cottonlike, or greasy debris in the external
auditory canal, sometimes on the tympanic membrane or in the residual space (after excision of
cholesteatoma);
increasing hearing loss.
A small part of affected patients (7%) have individual
immunosuppression as the result of an underlying disease or
569
its treatment. They can develop fatal acute invasive or
chronic invasive form of fungal infection.44,46 -51
2.
The rest of the patients (7%) have some kind of
immunodisturbance and are experiencing generalized skin diseases such as psoriasis or atopic
dermatitis rather than chronic otitis media.51 These
patients were treated with topical steroids for many
years. They had clinical signs of otitis externa only.
Clinical symptoms are seborrheic eczemalike skin
lesions with erythema and scaling or red papules
with a granular surface and fungal elements in the
epidermis. Lesions are itching in most cases.
Usually, these patients have a fungal colonization
of the external ear.
Diagnosis
Laboratory diagnosis includes direct microscopy, culture,
and, in selected cases, histopathology. The samples from the
auditory canal contain debris and secretion. From the external
ear, skin biopsies or swabs of pustules can be used for
mycologic culture. Surgical material from the tympanic
membrane, the residual space, and middle ear cavity may
be used for histopathology.
Mycology
One part of the samples has to be smeared on a
microslide with a drop of 15% to 30% KOH-containing
optical brighteners.1,2,51 After an incubation period of 2 to
24 hours, the slide is examined by fluorescence microscopy
at 330 to 390 nm. In addition, Giemsa and Gram stains may
be performed. Tightly packed septate hyphae are common in
specimens of debris from the auditory canal. In Giemsastained specimens from the auditory canal, numerous
hyperkeratotic (sometimes parakeratotic) epithelial cells,
some leukocytes, and hyphae of molds can be found.
The specimens should be inoculated directly into two
Sabouraud glucose agar tubes or plates for fungal culture.
One tube per plate is incubated at 378C and the other at
room temperature (228C) for 14 days. The molds have to be
subcultured on Czapek or malt agar. All investigations have
to be performed under safety conditions (class 2) to
minimize contamination with airborne germs.51
Histopathology
Surgical specimens of patients suspected of having
mastoiditis or cholesteatoma should be examined histologically. Special stains for fungi should be performed,
including periodic acid–Schiff, Grocott-Gfmfri methenamine-silver, and optical brighteners. Histological studies
demonstrate different fungal growth in the ear of affected
patients.45-51
1.
Chronic colonization of epithelium of auditory canal
and cholesteatoma. Fungal hyphae mostly of Asper-
570
gillus are observed between the horny lamellae of
cholesteatoma and in the stratum corneum of meatal
epithelium of immunocompetent patients. No inflammatory cellular response accompanied Aspergillus hyphae.45,51,52
2. Acute invasive and chronic invasive otomycosis.
These forms are often associated with fungal
infections of middle and inner ears.
Histological sections of a fragment from a tympanic
membrane or a residuum space of immunocompromised
patients show the matrix of cholesteatoma or epithelium of
an auditory canal with granulocytes and numerous fungal
hyphae. An invasive growth of mycelium in the blood
vessels or bones can be observed in patients with individual
immunosuppression or neutropenia.46 -51
Course and prognosis
The prognosis of immunocompetent patients is good.
Fungal infection in immunosuppressed patients can develop
into acute invasive or chronic invasive forms of otomycosis
with lethal consequence when not treated properly.
Treatment
The patients with chronic colonization should be treated
with intense debridement and cleansing in combination with
topical clotrimazole, imidazole, ciclopiroxolamine, amphotericin B, or nystatin. The treatment of immunocompromised patients is based on the application of combined
systemic and topical antifungal drugs after the surgical
debridement of infected tissue.51,54,55
Conclusions
Diagnosis of mold infections does not only need the
laboratory that is experienced in mycology but the medical
doctor who thinks about mold infection and performs
diagnosis with all the clinical skill needed. Many of falsenegative and false-positive bmold infectionsQ could be
avoided by careful patient’s history, clinical investigation,
and common sense in the interpretation of laboratory data.
Close communication between the dermatologist and the
mycologist in the laboratory is recommendable.
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