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Subcutaneous dematiaceous fungal infection

  • Author(s): Patel, Utpal
  • Chu, Julie
  • Patel, Rishi
  • Meehan, Shane
  • et al.
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Subcutaneous dematiaceous fungal infection
Utpal Patel MD PhD, Julie Chu MD, Rishi Patel MD, Shane Meehan MD
Dermatology Online Journal 17 (10): 19

Department of Dermatology, New York University, New York, New York

Abstract

Subcutaneous dematiaceous fungal infections, which include chromoblastomycosis and phaeohyphomycosis, are a heterogeneous group of clinical entities that are caused by dematiaceous or pigmented fungi found in soil. These infections have a wide spectrum of clinical presentations that depend largely on the specific causative organism and on the integrity of the host’s immune response. Treatment is challenging and involves a highly individualized plan that often combines both surgical and long-term medical treatment.



History

A 65-year-old man from Costa Rica with a history of a renal transplant, who was treated with chronic immunosuppressive therapy, was admitted for pneumonia to Tisch Hospital in December, 2010. The Dermatology Service was consulted for evaluation of an asymptomatic lesion on the right lower leg that began as a papule in 2007 and slowly evolved to become a nodule. One month prior to admission, the patient was started on voriconazole based on identification of fungal elements in a culture from the nodule. Tissues obtained from two punch biopsies were submitted for histopathologic examination and tissue culture analysis.

During the course of hospitalization, pneumonia was diagnosed on the basis of clinical and radioimaging studies and cefepime, levofloxacin, vancomycin, and amphotericin B were initiated. Bacterial lavage, sputum, and blood cultures failed to identify bacterial, fungal, or atypical mycobacterial organisms. After two weeks of treatment, clinical and radiographic evidence indicated resolution of pneumonia and the patient was discharged. The hospital course was complicated by transient acute renal failure related to amphotericin B.

Histopathologic evaluation of the nodule lead to a diagnosis of subcutaneous dematiaceous fungal infection (chromoblastomycosis versus phaeohyphomycosis). Although tissue culture was negative for bacteria, fungus, or atypical bacteria, an additional excisional biopsy was deferred because of concern for poor wound healing, owing to the location of the lesion and the history of diabetes mellitus and peripheral vascular disease. After a multidisciplinary discussion, a treatment plan was developed that combined medical and surgical therapy in an effort to balance the risks of surgery with those of adverse drug reactions that could result from the long-term use of antifungal agents with tacrolimus. Itraconazole was initiated in an attempt to decrease the size of the lesion prior to surgical excision; after two months of therapy, the size of the cutaneous nodule had decreased. The current plan is to perform surgical excision in the future followed by several months of systemic antifungal therapy.

Past medical history included diabetes mellitus, diabetic retinopathy, a renal transplant in 2007, coronary-artery disease, hypertension, and peripheral vascular disease. Medications include amlodipine, isosorbide mononitrate ER, furosemide, insulin, aspirin, calcitriol, mycophenalate mofetil, tacrolimus, pantoprazole, prednisone, and sulfamethoxasole-trimethoprim. The patient has no drug allergies.


Physical examination


Figure 1

A hyperpigmented, indurated nodule is present on the distal, posteriolateral aspect of the right leg.


Laboratory data

Complete blood work and comprehensive metabolic profile were normal.


Histopathology


Figure 2

Within a predominantly fibrotic dermis are foci of granulomatous inflammation with pigmented fungal spores. Fungal elements also are visualized on a periodic acid-Schiff-diastase stain.


Discussion

Subcutaneous dematiaceous fungal infections, which include chromoblastomycosis and phaeohyphomycosis, are a heterogeneous group of clinical entities caused by dematiaceous or pigmented fungi that are found in soil. These infections have a wide spectrum of clinical presentations that depend largely on the specific causative organism and on the integrity of the host’s immune response. Treatment is challenging and involves a highly individualized plan that often combines both surgical and long-term medical treatment.

Chromoblastomycosis and phaeohyphomycosis are both caused by pigmented fungi and share a number of clinical features and causative organisms, yet are considered two distinct clinical entities. Chromoblastomycosis is a subcutaneous infection with highest prevalence in the tropics; it is typically seen in immunocompetent hosts and results from traumatic inoculation of skin by pigmented fungi. The principle causative agents are fungi of the genera Fonsecaea (tropical forests), Cladophialophora (dry climates), and Philalophora [1]. The disease is most commonly observed in agriculturists on the lower legs, which likely explains the observed propensity for men of lower socioeconomic status. Chromoblastomycosis typically presents with an asymptomatic papule or nodule that develops slowly over years into a localized verrucous plaque that expands and leaves behind a central sclerotic or keloidal scar. The lesion may have characteristic black dots on the surface, which represent the host’s attempt at transepidermal elimination of fungal elements. The disease most often remains localized, but satellite lesions from autoinoculation and lymphatic spread have been documented [2]. Secondary complications may result from bacterial superinfection, ulceration, secondary lymphedema, and, rarely, development of a squamous-cell carcinoma. In an immunocompromised state, there is a risk of extension into underlying skeletal muscle and bone [3]. The diagnosis of chromoblastomycosis rests on identification of thick-walled, multiseptate, brown, sclerotic cells termed Medlar bodies, copper pennies, or muriform cells. These pathognomonic features can be observed in tissue biopsy specimens or by direct microscopic examination of a scraping of black dots from the surface of the nodule with 10 percent potassium hydroxide. Identification of the causative fungal species can be achieved by tissue culture but is not reliably positive.

Phaeohyphomycosis describes a heterogeneous group of fungal infections that are caused by over 100 species and 60 genera of dematiaceous that are fungi found in soil worldwide, with varied clinical presentations that are greatly influenced by the immune status of the host [4]. Common causative agents of phaeohyphomycosis include fungi of the genera Exophiala, Wangiella, Bipolaris, Alternaria, and Phialophora [5]. The most common clinical presentations in immunocompetent hosts include localized cutaneous infection (superficial or subcutaneous), fungal sinusitis, allergic bronchopulmonary mycosis (similar to the presentation of allergic bronchopulmonary aspergillosis), and, rarely, fatal brain abscess. The subcutaneous lesions of phaeohyphomycosis typically result from direct inoculation via trauma to exposed skin, and, in immunocompetent patients, most commonly present as a single, inflammatory, cystic or indurated plaque [6]. In immunocompromised patients, phaeohyphomycosis is increasingly being recognized as an opportunistic infection [7]. In these individuals, the clinical presentation is variable and ranges from an isolated nodule to disseminated, indurated plaques, nodules, escars, and ulcers. In addition, immunocompromised patients are at risk for locally invasive phaeohyphomycosis, and, rarely, but often fatal, pneumonia or disseminated disease.

Treatment for both chromoblastomycosis and phaeohyphomycosis can be challenging and often requires a combination of medical, surgical, cryotherapy, or thermal therapy. With early or localized disease, the goal of treatment can be curative, but with extensive disease, treatment goals are to reduce disease burden, limit spread, and prevent complications. Medical therapy consists of long courses (months to years) of antifungal agents, specifically itraconazole (200 to 400 mg daily or pulse dosing of 400 mg daily for one week every month) and terbanifine (500 to 1000 mg daily). Combination therapy with itraconazole and terbanifine has been shown to be synergistic [8]. Newer agents, such as voriconazole and posaconazole, have shown promise, but experience is limited [9]. Fluconazole, ketaconazole, amphotericin B, and flucytosine are not indicated either because of poor efficacy or a poor side effect profile [3]. Medical therapy is often combined with surgical and/or physical destructive methods, which include thermotherapy (daily for months) or cryotherapy to reduce disease burden, decrease treatment duration, and improve efficacy. Cryotherapy is effective, but generally requires multiple treatment cycles [10, 11, 12]. Irrespective of the treatment modality, drug therapy should be continued for several months after cure to prevent relapse. Reported overall cure rates for phaeohyphomycosis could not be found in the literature, but for chromoblastomycosis they range from 15 percent to 80 percent [13]. Standard-of-care treatment guidelines have not be been established because of a lack of studies and a lack of correlation between in vitro efficacy and clinical efficacy. Current understanding is based on individual case reports or small case series [14, 15, 16, 17]. In addition to these limitations, the varied clinical presentation and comorbidities dictate that the treatment for chromoblastomycosis and phaeohyphomycosis be individualized.

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