Phaeohyphomycosis is a rare, opportunistic infection caused by melanized fungi that
predominates in tropical climates.1, 2 The increase in the number of organ transplant
recipients (OTRs), in conjunction with improvement in their long-term treatment, has
led to an increase in the incidence of phaeohyphomycosis.1, 3, 4, 5, 6, 7 Phaeohyphomycosis
has a wide range of clinical presentations, which are associated with the immune status
of the host.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 We describe 7 cases of phaeohyphomycosis
in OTRs, which clearly demonstrate that the clinical presentations can have profound
variations and that treating this infection in this specific patient population can
Materials and methods
We present a case series of 7 OTRs with phaeohyphomycosis that have been followed
up with our specialized dermatologic clinic for more than 4 years. Their clinical
presentations and treatment approaches are discussed. Table I summarizes the findings.
A 57-year-old male farmer presented with multiples nodules with a sporotrichoid pattern
on his lower right limb that developed 2 years after kidney transplantation (Fig 1).
There were no signs of systemic symptoms. His immunosuppressive medications included
azathioprine, tacrolimus, and prednisone. A direct examination found dematiaceous
filamentous fungi, and culture yielded Exophiala sp. Histopathologic analysis found
granulomatous dermatitis, and fungal melanized structures were seen through Fontana-Masson
stain. Imaging studies ruled out internal foci of infection. He was initially treated
with 200 mg twice a day of voriconazole, which was discontinued very soon because
of severe hyponatremia. Itraconazole, 200 mg twice a day was started afterwards, which
was accompanied by severe headache, anorexia, and weight loss. After reducing the
tacrolimus dose, the symptoms gradually resolved. The lesions were surgically removed.
Itraconazole was continued for 6 months, and no relapse has occurred so far.
A 59-year-old male gardener presented with an erythematous violaceous plaque on his
right thigh that developed 18 months after kidney transplantation (Fig 2). His immunosuppressive
medications included mycophenolate mofetil, tacrolimus, and prednisone. Direct examination
of the biopsy specimen found several melanized septate hyphae. Microscopic examination
of the fungal colony identified Exophiala sp. The biopsy specimen underwent Fontana-Masson
and Gridley stains, which also confirmed the diagnosis of phaeohyphomycosis. Treatment
included surgical removal of the lesion along with 200 mg twice a day of itraconazole
for 4 months. There was no recurrence 2 years after completion of the treatment.
A 43-year-old male rural worker presented with a nodule over his left knee that evolved
2 years after cardiac transplantation. His immunosuppressive medications included
mycophenolate mofetil, cyclosporine, and prednisone. Direct microscopy examination
of the biopsy specimen found dematiaceous hyphae, and microscopic examination of fungal
colony found Exophiala sp (Fig 3, A and B). The histopathology findings showed neutrophilic
infiltrate and giant cells with dematiaceous hyphae. The patient was treated with
surgical excision followed by itraconazole, 200 mg/d orally for 2 months. He has been
undergoing follow-up for more than 2 years without recurrence.
A 64-year-old female maid presented an asymptomatic nodule on her right elbow that
had grown 9 months after cardiac transplantation. There was no history of local trauma.
Her immunosuppressive medications included cyclosporine, mycophenolate mofetil, and
prednisone. The lesion was surgically removed. Direct microscopy examination of the
biopsy specimen found dematiaceous hyphae, and microscopic analysis of fungal culture
showed Exophiala sp. The histopathologic examination found granulomatous inflammatory
infiltrate with multinucleated giant cells (Fig 4). Filamentous fungi were seen through
Grocott stain (Fig 5). She has undergone follow-up for more than 2 years without recurrence.
A 42-year-old male retired policeman presented with an asymptomatic hyperkeratotic
tumor on his right leg that evolved 11 months after cardiac transplantation. His immunosuppressive
medications included mycophenolate mofetil, tacrolimus, and prednisone. Direct microscopy
of the biopsy specimen found dematiaceous filamentous fungi (Fig 6), and fungal culture
yielded Exophiala sp. Histopathology found a cystic structure with multinucleate giant
cells, and dematiaceous filamentous fungi were seen on Fontana-Masson stain. Surgical
excision was performed. Itraconazole, 200 mg twice a day, was started before surgery
and maintained for 4 months. He has undergone follow-up for more than 2 years without
A 34-year-old female hair stylist presented with a verrucous plaque between her first
and second right toes that had grown 10 months after kidney transplantation (Fig 7).
Her immunosuppressive medications included tacrolimus, mycophenolate mofetil, and
prednisone. Direct examination of the biopsy specimen found dematiaceous filamentous
fungi, and microscopic study of culture found Exophiala sp. Histopathologic analysis
found inflammatory infiltrate with multinucleated giant cells. Dematiaceous hyphae
were seen through Fontana-Masson stain. The patient refused treatment and became lost
A 43-year-old male mason presented with asymptomatic erythematous plaques on his right
leg and on the index finger of his left hand that had grown 16 months after cardiac
transplantation (Fig 8). His immunosuppressive medications included mycophenolate
mofetil, tacrolimus, and prednisone. Direct examination of the biopsy specimens found
dematiaceous fungi, and microscopic analysis of culture found Exophiala sp. Histology
confirmed the presence of fungal structures along with a granulomatous reaction. All
lesions were surgically removed. In addition, the patient was treated with 200 mg
twice a day itraconazole for 6 months, which had started just before surgery. The
tacrolimus dose was adjusted accordingly. He has undergone follow-up for more than
2 years without recurrence.
Phaeohyphomycosis is a group of rare opportunistic fungal infections predominantly
affecting the skin, although systemic disease can occur.1, 2, 3, 4 The incidence of
phaeohyphomycosis in OTR is approximately 9%, and disease usually occurs in the first
few years after transplant.1, 2, 8 Phaeohyphomycosis developed in all of our patients
within the first 2 years after transplant.
The incidence of phaeohyphomycosis seems to be increasing as a result of increasing
numbers of OTRs and scientific advances made in immunosuppressant medications.4, 5,
6, 8 Regarding the specific immunosuppressant drug, it seems that calcineurin inhibitors
such as tacrolimus are more associated with greater susceptibility to fungal infections,
which later can become recurrent.1, 4, 5, 7 All of our patients were taking this medication.
Although it has been published that phaeohyphomycosis is more frequent in kidney transplant
recipients,1, 4, 6, 7, 8, 10 we did not find a statistical difference between kidney
and heart transplants in our series. This finding may be owing to the limited number
of patients. However, we stress that all patients, regardless of the type of organ
received, were under heavy immunosuppressive therapy.
Diagnosis of phaeohyphomycosis is complicated by its highly variable clinical presentation.1,
2, 3, 4, 5, 6, 7 In our patients, the diagnosis was based on clinical, microbiologic,
and histopathologic studies. We observed a wide spectrum of clinical lesions including
nodules, cysts, tumors, and verrucous plaques, mostly with subcutaneous involvement.
The diversity of lesions presented in this series may reflect the differences in disease
progression, variable host response, and degree of the immunosuppression.
Despite that there are more than 100 species of fungi associated with this disease,
there is still no correlation between the etiologic agent and morphology of lesions.3,
Exophiala sp was the only agent identified in this group of OTRs. This species is
ubiquitous in nature and typically causes infections via traumatic implantation.9,
10 All of our patients had lesions on the limbs, which can be attributed to direct
inoculation of the fungus into damaged skin after contact with a contaminated fomite
The treatment of phaeohyphomycosis is a challenging issue, as there is no standardized
treatment and a high possibility of dangerous drug-drug interactions.1, 4, 6, 7 Surgery
is likely the best treatment for well-circumscribed lesions, but additional medical
treatment is recommended to avoid local sporotrichoid dissemination and to treat concomitant
subclinical lesions.4, 7, 10 In the selected patients, a cure can be achieved by surgery
alone as could be seen in case 4. However, we do believe that surgery can be an important
adjuvant therapeutic method that should be associated whenever possible with antifungal
Itraconazole was the antifungal medication used in most of our patients and was associated
with high cure rate. Itraconazole, which is fungistatic and inhibits ergosterol synthesis,
seems to be the most effective agent, especially against Exophiala sp.9, 10
One of the most important points to consider in the use of broad-spectrum azoles in
OTRs is that these drugs are strong cytochrome CYP3A4/5 inhibitors and may cause major
drug-drug interactions with calcineurin and mammalian target of rapamycin (mTOR) inhibitors.1,
4, 6 Because these immunosuppressive drugs are characterized by a narrow therapeutic
window, these drug-drug interactions could lead to clinical complications as also
clearly seen in the first case. It is important to closely monitor tacrolimus concentrations
and be on the look out for signs of drug-related toxicity.
Because of the increased incidence of phaeohyphomycosis in OTRs, it is important that
all clinicians involved in solid organ transplants always consider the possibility
of this disease in allograft recipients with skin lesions. The high degree of clinical
suspicion is essential to establish the correct diagnosis and to start treatment promptly
to avoid serious complications and organ rejection.