ARTICLE
Skin infections due to moulds are very rare entities.
Primary infections occur after a direct inoculation of the fungus into
breaks of the skin and open wounds, e.g. burn wounds or diabetic
gangraene [1]. Infecting or colonizing causing agents may be Fusarium,
Scedosporium, and, particularly Aspergillus (A.) species. Increasingly,
primary cutaneous aspergilloses (CA) are seen in AIDS patients, but also
in patients suffering from septic, chronic granulomatosis. Besides, secondary
CA caused by haematogeneous spread from invasive aspergillosis of the
lungs or Aspergillus sepsis may develop. Causative agent is A.
fumigatus, rarely A. flavus may be found. A. flavus
infections show a poor response to common antifungals in vivo,
in particular against intravenously administered amphotericin B. This
may be due to a diminished in vitro susceptibility of A. flavus
against this polyene antifungal.
Case report
Starting in February 1999, a 64-year-old patient suffered from a hypoblastic
myelodysplastic syndrome (MDS) which was characterized by pancytopenia
and cytogenetic aberrations. In June 1999, after the development of a
secondary acute myeloblastic leukaemia, induction chemotherapy was performed,
but only partial remission could be achieved. Thereafter, the patient
received a second induction therapy followed by an allogenic (related,
from his sister) peripheral blood stem cell transplantation (HLA haploid)
conditioned with 2 Gy TBI (total body irradiation) and fludarabine in
August 1999. Skin lesions of a limited graft versus host disease developed.
After haematopoietic reconstitution in September 1999, chest pain and
dyspnoea occurred. A left-sided heart failure was found. Pneumonia had
to be suggested. Chest computer tomography revealed multiple diffuse and
central confluent infiltrations predominantly in the right but also in
the left lung lobe, suggestive for aspergillosis lesions. Bronchoscopy
was performed. In both the bronchoalveolar lavage fluid and bronchial
secretion Aspergillus-Antigen (Pastorex®, Sanofi
Diagnostics Pasteur, Marnes-de-la-Coquette, France) was detected, additionally
A. flavus grew on Sabouraud´s-4% dextrose agar (Fig.
1a). The respiratory symptoms worsened with the development of more
extensive pulmonary infiltrates involving both lung fields (Fig.
1b). High frequency oscilating ventilation was necessary.
The patient's general condition deteriorated despite maximal support
with resulting multi organ failure. The acute cardiac failure was treated
with high dose catecholamines, renal failure was treated by haemofiltration.
A striking neutropenia was remarkable. With the suspicion of an invasive
pulmonary aspergillosis, antifungal treatment was started with amphotericin
B (50 mg/d), than changed to Ambisome® (liposomal encapsulated
amphotericin B, 100 to 150 mg/d).
On the sides and back 4 or 5 erythematous to violaceous rounded nodular
lesions appeared, which tended to haemorrhage (Figs.
2a and b). Biopsy from these lesions was performed. At 37° C
a mould with yellowish-green thallus, oval and round or spherical vesicles
with biserate phialides and rough-walled conidiophore stipes grew from
skin tissue extremely fast (over night). Echinulate spherical and subspherical
conidia were visible. Based on these characteristics species differentiation
was A. flavus (Fig.
3).
Pathohistologically, a skin biopsy specimen showed multiple septated
hyphae in a typical pattern with 45-degree dichotomous branching within
the corium and subcutaneous tissue, using both PAS (Figs.
4a-c), and Grocott staining.
The in vitro susceptibility testing of the isolate using a microdilution
method with HR (high resolution) medium (Oxoid/Unipath, Basingstoke, Hampshire,
England) revealed the following values of minimum inhibitory concentration
[mug ml-1]: amphotericin B 2, Ancotil® (5-fluorocytosine)
medium susceptible, Sempera® (itraconazole) 0.5, and Diflucan®
(fluconazole) 64. Despite high dosage antifungal therapy with liposomal
amphotericin B, the patient died in October 1999 due to Aspergillus
pneumonia associated with multiple aspergilloma of the lungs and generalized
aspergillosis with disseminated haematogeneous spread to the heart, brain,
and skin.
At autopsy, in all lung lobes multiple aspergillomata with diameters
from 0.5 to 4 cm were seen together with confluent mycotic bronchopulmonic
lesions. Within the left ventricular wall of the heart an aspergilloma
with 0.5 cm diameter was found. The left ventricular septum and dorsal
wall of the heart contained six aspergillomata, showing diameters from
1 to 1.5 cm (Fig. 5).
The periphery of these aspergillomata showed necrotic zones. Septicopyemic
abscesses with Aspergillus infiltrations were found in the skin.
In the brain multifocal intracerebral pyogenic focal encephalitis caused
by Aspergillus infection was seen. Due to septicopyemic vascular
occlusions consecutive haemorrhagic infarctions in adjacent brain tissue
had developed. This may be interpreted as an alternative cause of death.
Discussion
Cutaneous aspergillosis: frequency
A high percentage of cases with CA have been reported in neutropenic
cancer patients. It has also emerged as a significant infection among
a variety of immunocompromised patients, including neonates, after organ
or bone marrow transplantation, chronic granulomatous disease, autoimmune
diseases receiving corticosteroids, and patients with burn wounds [2].
Despite an increasing occurrence of invasive aspergillosis, predominantely
of the lungs, there are relatively less frequent reports on CA in the
recent literature. Aspergillosis is the second most frequent life-threatening
mycotic infection in patients suffering from haematological malignancies.
D'Antonio et al. [3] evaluated skin infections caused by Aspergillus
in patients with haematological disorders. Twelve cases of CA occurred
among 4,448 consecutive patients with acute leukaemia. Three additional
cases were seen in chronic myeloid leukaemia and myelodysplastic syndrome.
Cutaneous involvement occurred in 4% of patients with documented Aspergillus
infection. Up to 1998 more than 50 cases of CA in cancer patients have
been reported in the literature [1]. In addition, CA has been estimated
to occur in up to 10% of non-HIV patients with disseminated Aspergillus
infection and in 4% of haemotological patients with invasive pulmonal
aspergillosis and secondary haematogenous spread [3]. It should be mentioned
that from our point of view this percentage of 10% seems to be too high.
Recently, Kaiser et al. [4] carefully described the clinical
feature of 35 proven cases of invasive aspergilloses. Thirty-three patients
(94%) had pulmonary apsergillosis, other involved organs and tissues were:
heart 4 (11%), liver 3 (8.5%), kidney 3 (8.5%), spleen 2 (5.7%), and both
skin, mediastinum, and central nervous system one each (corresponding
to 2.9%).
Primary cutaneous aspergillosis
Primary CA usually involves sites of skin injury and occurs as traumatic
inoculation. In particular, burns of second and third degree may be colonized
or infected by moulds, in the first line by Aspergillus species
[5-9]. Primary skin infection by Aspergillus has been reported
at intravenous catheter sites. In particular, adhesive and occlusive dressings
and tapes for venous access devises, e.g. Tegaderm®,
may be contaminated by Aspergillus spores [10]. Cases of primary
aspergillosis of the skin in patients with acquired immunodeficiency syndrome
have been reported, all of them with a history of maceration of the skin
from the use of adhesive tape or intravenous catheters [11]. Other reports
demonstrated primary CA in surgical wounds, damaged skin, sites of venesection
and pyoderma gangraenosum [12, 13].
A recent paper by Munn et al. [14] described two previously fit
young people who were admitted to the neurosurgical unit following spinal
trauma with resulting tetraplegia. They were immunocompromised because
of high-dose corticosteroids and lymphocytopenia. Primary CA as erythematous
plaques studded with pustules mimicking cutaneous Candida infection
developed on the back. The cause was that the skin remained occluded by
the bed sheets despite a special spinal rotating bed.
Thakur et al. [15] were the first who described a patient with
recalcitrant pemphigus vulgaris that required aggressive immunosuppression
and in whom invasive, necrotizing CA developed at multiple sites, which
was followed by septic shock and death.
Primary CA is usually seen in immunocompromised hosts. However, even
in immunocompetent patients a primary CA has been reported [16]. Lakhanpal
et al. [17] recently reported a further immunocompetent patient
with CA. They were able to find only five further reports on CA in immunocompetent
hosts to date.
In patients with human immunodeficiency virus infection CA occur with
emerging frequency [18]. In 2000, Murakawa et al. [19] described
11 patients with CA in HIV-infected patients and reviewed 13 additional
cases that they found published in the literature. All reported patients
had very low CD4 counts with a median of 0.006 x 109/l,
indicating that they were in an advanced stage of infection. Interestingly,
not all HIV patients were neutropenic as is characteristic for the development
of an aspergillosis. Thus, the major risk factor of aspergillosis in HIV-infected
patients seems to be neutropenia caused by myelotoxic drugs, e.g.
zidovudine and ganciclovir. A cytomegaly virus infection may be associated
[18, 20].
Secondary cutaneous aspergillosis
Secondary cutaneous infections due to Aspergillus species are
commonly a result of haematogenous seeding from a primary focus of infection,
most often the lung, occurring in highly immunocompromised hosts [1].
More rarely these secondary lesions may develop from contiguous extension
to the skin from underlying structures, e.g. the lungs. The lesions
may be single or multiple, may not be tender, and occur most commonly
on the extremities [10]. On the contrary, the patient described here was
affected exclusively on his trunk.
Non-HIV-related secondary CA lesions initially appear as erythematous
macules or papules that evolve to haemorrhagic bullae or ulcerative nodules
[21]. Histological examination reveals invasion of local blood vessels
and infarction of the skin, corresponding to the visual appearances [22].
Skaria et al. [23] described a metastatic Aspergillus panniculitis
in the case of blastic transformation of a myelodysplastic syndrome and
agranulocytosis. The skin lesion showed a single subcutaneous inflammatory
nodule, which was clearly demonstrated by histology to be of embolic origin.
Interestingly, A. flavus is more often present in primary CA,
whereas most disseminated infections are caused by A. fumigatus
[24]. Also, Lakhanpal et al. [17] found that primary CA is usually
caused by A. flavus and A. niger. In accordance with that,
in this case of a secondary CA, we were able to isolate A. flavus
both from bronchial secretion and bronchoalveolar lavage fluid and later
on from a skin tissue sample. In addition, occasionally further Aspergillus
species have been reported in CA. Tritz and Woods [25] described a
disseminated infection with A. terreus in an immunocompromised
host suffering from acute myeloid leukaemia, with haematogenous spread
of the mould to the skin. More recently, A. chevalieri has been
reported to cause morphologically distinct skin lesions, which appear
erythematous, hyperkeratotic, and vesiculopapular in nature [26].
James et al. [27] used a repetitive DNA probe to type clinical
and environmental isolates of A. flavus from a cluster of cutaneous
infections in a neonatal intensive care unit. The probe was used to investigate
two cases of cutaneous A. flavus infection in low-birth-weight
infants. Both infants were transported by the same ambulance and crew
to the hospital on the same day. A. flavus strains of the same
genotype were isolated from both infants, from a canvas bag used to store
the tape in the ambulance, and from the tape tray in the ambulance isolette.
Treatment of cutaneous
aspergillosis
It appears reasonable to use itraconazole for the treatment of patients
for whom primary CA has been localized at least several centimetres from
a vascular catheter exit site and for whom there is no evidence of extracutaneous
aspergillosis [28]. Patients receiving itraconazole should be monitored
carefully. Thus, if there is any sign of a diminished response to this
triazole, the management regimen should be changed to intravenous amphotericin
B.
In their excellent minireview concerning CA, Burik et al. [1]
do not recommend the use of itraconazole as a first line therapy for cutaneous
Aspergillus infections involving vascular catheter exit sites or
tunnel infections, secondary CA, or extensive primary cutaneous disease.
These severe infections require the intravenous application of amphotericin
B. Consequent surgical debridement improves the clinical outcome of CA.
Recently, Lass-Flörl et al. [29] demonstrated that in
vitro testing of susceptibility to amphotercin B is a reliable predictor
of clinical outcome in invasive aspergillosis. Irrespective of species
- A. fumigatus, A. flavus and A. terreus - all six
out of 29 patients with isolates against which the minimum inhibitory
concentration was < 2 mug/ml survived, whereas most (22/23) of those
with isolates resistant to amphotericin B with MIC values >= 2 mug/ml
- as it was the case in our patient - died.
Article accepted on 16/8/01
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