Rare and Emerging Fungal Pulmonary Infections

Jay B. Varkey, MD; John R. Perfect, MD

Disclosures

Semin Respir Crit Care Med. 2008;29(2):121-131. 

In This Article

Dematiaceous Molds: Phaeohyphomycosis

Phaeohyphomycosis is a loosely defined term used to group infections caused by molds (and a few yeasts) that produce dark cell walls. As with the agents of hyalohyphomycosis, the list of dematiaceous fungi is both long and taxonomically diverse. These organisms are characterized by the presence of a pale brown to dark melanin-like pigment in the cell wall. This group of fungi is found in soil, air, plants, and organic debris. The number of genera and species of fungi causing phaeohyphomycosis is quite large. This section focuses on the disease entities caused by these diverse organisms.

Mycetoma

Like the hyaline molds, dematiaceous molds are a cause of mycetomas: chronic granulomatous infection marked by sinus tracts and production of tissue grains. Although mycetomas caused by hyaline molds produce pale white/yellow grains, mycetomas that form from the dematiaceous molds are marked by dark black grain production. Among the black fungi causing dark-grained mycetoma, the most common are Madurella mycetomatis, M. grisea, Leptosphaeria senegalensis, Pyrenochaeta romeroi, and Exophiala jeanselmei. Diagnosis is clinical -- direct microscopy and culture of grain obtained from a sinus tract confirms the causative organism. Treatment typically requires surgical resection and antifungal treatment. In vitro, voriconazole has good activity against many of the agents of eumycetoma (fungal mycetoma).[73]

Chromoblastomycosis

Chromoblastomycosis (chromomycosis) is a chronic localized fungal infection of the skin and subcutaneous tissue that produces raised scaly lesions, usually of the lower extremities. Several dematiaceous fungi cause chromoblastomycosis. Fonsecaea pedrosoi is the most common causative organism, although disease is also caused by F. compacta, Cladosporium carrionii (syn., Cladophialophora carrionii), Phialaphora verrucosa, and Rhinocladiella aquaspersa. Most cases arise in tropical and subtropical regions. Microscopic examination of skin scrapings can provide rapid diagnosis because the characterisitic muriform cells (also called "copper penny" or sclerotic bodies) may be seen in potassium hydroxide preparations, especially those containing black dots.[74] Treatment typically requires antifungal therapy combined with either or both surgical resection and cryotherapy with liquid nitrogen.[74] Terbinafine has produced excellent results in the treatment of chromoblastomycosis.[75] The newer extended-spectrum triazoles may also be useful to treat chromoblastomycosis. In vitro susceptibility testing has shown that the minimum inhibitory concentrations for voriconazole for F. pedrosoi and F. compacta are lower than those observed with itraconazole.[73]

Subcutaneous Phaeohyphomycosis

The dematiaceous fungi that cause subcutaneous phaeohyphomycosis are diverse -- the most common pathogens are Exophiala jeanselmei, Wangiella dermatitidis, Bipolaris, Phialophora, and Exserohilum species. Subcutaneous phaeohyphomycosis typically begins as a single red nodule, usually on the extremities. In the immunocompetent person, an indolent, painless expansion in the skin and subcutaneous tissue occurs and can occasionally develop well-formed cysts.[76] In immunosuppressed patients local progression and extension can occur rapidly producing scaly, crusty skin lesions or ulcers. Diagnosis of subcutaneous phaeohyphomycosis is usually made after surgical excision or biopsy by the demonstration of pigmented hyphae histologically and by the isolation and identification of compatible etiologic fungi.[77] Management of subcutaneous phaeohyphomycosis usually involves surgical treatment with or without the use of an antifungal agent.[78]

Keratitis

Dematiaceous fungi are the third most common cause of fungal keratitis after Fusarium and Aspergillus.[79] Among the dematiaceous fungi causing keratitis, Curvularia, Bipolaris, and Exserohilum species are the most common causative organisms. Dematiaceous fungi are a particularly significant cause of fungal keratitis in tropical areas, and most cases are associated with trauma from fungus-contaminated plant material. Clinical features typically include redness, photophobia, and decreased visual acuity accompanied with a yellow-white infiltrate typically limited to the central cornea. Diagnosis is made by isolating and identifying the causative organisms by histopathology and culture of corneal scrapings. Most cases are treated with topical polyenes such as natamycin and amphotericin B. Severe cases may require adjunctive therapy with an oral azole. In persons failing medical therapy, surgery, including penetrating keratoplasty, may be necessary.[80]

Sinusitis

Sinusitis may be caused by a wide variety of fungi. Among the dematiaceous molds, Bipolaris, Curvularia, Exserohilum, and Alternaria species represent the most common causative species.[81] Disease can present as allergic sinusitis or as large fungus balls in the sinus cavities. Treatment typically requires surgical debridement. In cases of fungus balls, antifungal agents do not appear to be of additional benefit unless invasion of the surrounding mucosa or bone is demonstrated.[82,83] Along with Aspergillus species, the phaeohyphomycetes are the main etiologic agents for cases of allergic fungal sinusitis, and the management of this entity still lacks clear guidelines.

Allergic Bronchopulmonary Mycoses

This is a fairly recent concept, similar in presentation to allergic bronchopulmonary aspergillosis (ABPA), which is typically seen in patients with asthma or cystic fibrosis.[84] The most common fungi are Bipolaris and Curvularia species. Therapy is primarily systemic steroids, usually prednisone at 0.5 mg/kg/d for 2 weeks, followed by a slow taper over 2 to 3 months or longer, if necessary. Itraconazole has been used as a steroid sparing agent, but its efficacy is not clear, and routine use of itraconazole is not specifically recommended.

Pneumonia

Nonallergic pulmonary disease with the black molds usually occurs in immunocompromised patients and may be due to a wide variety of species commonly found in the environment (including Bipolaris, Ochroconis (Dactylaria), Fonsecaea, and Chaetomium species). However, cases in immunocompetent patients may also be seen.[85] It is extremely important to perform proper identification of the black mold from nonsterile sites like fluid from bronchoalveolar lavage (BAL). The growth of Cladosporium, species even in lung transplant recipients, is unlikely to be causing disease, but other black molds like Dactylaria would cause much more concern about potentially invasive lung disease or dissemination. Therapy usually consists of intravenous amphotericin B or oral itraconazole initially, followed by itraconazole for a more prolonged period. Experiences with voriconazole and posaconazole are anecdotal but recent experience would suggest that these agents would be satisfactory for most of these infections, and echinocandins might be used in combination for serious or refractory cases. Mortality rates are high in immunocompromised patients.

Central Nervous System Infection

Although rare, CNS infection is one of the best-described and frequently fatal syndromes produced by the dematiaceous molds. A retrospective analysis of 101 reported cases of CNS phaeohyphomycoses found that over half occurred in immunocompetent patients, with Cladophialophora bantiana the most common species isolated.[86] Disease is also caused by Ramichloridium mackenziei, Ochroconis gallopavum (Dactylaria gallopavum), Wangiella dermatitidis, Bipolaris spicifera, B. hawaiiensis, and Chaetomium species. CNS infection from dematiaceous molds typically presents with indolent headache, low-grade fever, and development of focal neurological signs. Often, it requires surgical intervention and the use of a combination of antifungal agents for successful management.

Disseminated Infection

This is the most uncommon manifestation of infection seen with dematiaceous fungi. There are case reports of several different dematiaceous molds that have caused disseminated disease, including Bipolaris species and Wangiella dermatitidis. In a recent review, most patients were immunocompromised, though occasional patients without known immunodeficiency or risk factors developed disseminated disease as well,[87] and infections have occurred with contaminated devices or biological products. In contrast to most invasive mold infections, blood cultures are positive in over half the cases of disseminated phaeohyphomycosis -- this is likely related to adventitial yeast forms in tissue. There are no specific antifungal regimens associated with improved survival in disseminated infection. Despite combination regimens including itraconazole, voriconazole, posaconazole, flucytosine, echinocandins, and amphotericin B being tried, the mortality rate for disseminated disease remains < 70%.[86,87] In a case report, posaconazole successfully cleared fungemia in a patient with no known immunosuppression and a 12-year history of relapsing phaeohyphomycosis who developed disseminated Exophiala spinifera during pregnancy.[88]

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