LAS VEGAS — Dematiaceous, or darkly pigmented, fungi are emerging as an important cause of disease, and certain types of infections with these pathogens are associated with high rates of mortality, even among the immunocompetent, Dr. Sanjay G. Revankar said at a meeting on fungal infections sponsored by Imedex.
This is a heterogeneous group of fungi that includes more than 60 genera and 100 species found worldwide in soil and air. Melanin, present in the cell wall, provides the coloration of these pathogens and appears to be a virulence factor, providing protection from free radicals, hydrolytic enzymes, and ultraviolet damage.
One of the clinical syndromes associated with various species of dematiaceous fungi increasingly being seen is phaeohyphomycosis. Most of the species implicated are opportunists, but some may be true pathogens, said Dr. Revankar of the University of Texas Southwestern Medical Center, Dallas.
The diagnosis of phaeohyphomycosis requires expert interpretation of colony and microscopic morphology. The typical histologic findings include irregularly swollen hyphae and yeastlike forms. In contrast to many other fungi, there are no adequate serologic or antigen tests for the species that cause phaeohyphomycosis, he said.
The range of clinical syndromes comprising phaeohyphomycosis includes the following:
▸ Superficial infections. These typically manifest as subcutaneous nodules appearing after minor trauma to the skin and inoculation with species of Exophiala, Alternaria, or Phialophora. Successful treatment often requires only excision, although an azole is sometimes also given.
▸ Allergic disease. Most cases of sinusitis and bronchopulmonary mycosis are caused by species of Curvularia or Bipolaris. Sinusitis is characterized by the presence of allergic mucin and elevated IgE; treatment includes surgery plus corticosteroids. Bronchopulmonary mycosis is associated with elevated IgE or eosinophilia, and treatment relies on corticosteroids. Antifungal therapy is not routinely used for these infections, Dr. Revankar said.
▸ Pneumonia. This has been seen most in immunocompromised patients, and may be characterized by hemoptysis. Among the pathogens implicated are species of Exophiala and Chaetomium. Lipid amphotericin B is the preferred treatment for these seriously ill patients, followed by an azole if the patient stabilizes, but mortality is high, he said.
▸ CNS phaeohyphomycosis. This infection shows a 3:1 male predominance and has been reported worldwide. “What is really unusual is that more than half of patients seem to have no risk factors—no chemotherapy, HIV, or other immunodeficiency,” Dr. Revankar said. In a series of 101 patients with CNS infection, the classic triad seen with bacterial brain abscess—fever, headache, and neurologic deficits—was present in fewer than 5% of patients (Clin. Infect. Dis. 2004;38:206–16). Overall mortality was 72%.
Many species have been isolated in CNS infections, but in nearly half of cases Cladophialophora bantiana was implicated.
There was little evidence of efficacy for any particular antifungal regimen in these patients with CNS disease. A combination of amphotericin B, 5-fluorocytosine, and itraconazole was associated with improved survival, but only six patients in the series received this combination. Voriconazole and posaconazole have shown in vitro activity, but there is very little clinical experience with these agents for this indication, he said.
▸ Disseminated phaeohyphomycosis. “This has been seen increasingly during the past 10–15 years, probably reflecting the type of patients we are seeing, such as those who are immunocompromised from treatment for other diseases,” Dr. Revankar said. Prior cardiac surgery, particularly involving bioprosthetic valve replacements, also has been identified as a risk factor.
In a series of 72 patients, fever was present in only 76%. Skin lesions were seen in 33%, sepsis in 11%, and eosinophilia in 11% (Clin. Infect. Dis. 2002;34:467–76). Blood cultures were positive, most commonly revealing Scedosporium prolificans in more than half of patients. Most of the cases were in Spain and Australia.
Overall mortality was 79%. In the immunocompromised it was 84%, and in the immunocompetent it was 65%. S. prolificans is resistant to all available agents, and no single drug or combination of drugs was associated with improved outcome in this series. In two cases, however, the combination of an azole plus terbinafine was successful. “I wouldn't recommend this routinely, but if you have no other options it might be something to consider. Terbinafine is not considered a particularly useful systemic drug because of its pharmacokinetics, but in these cases there really is not much else left,” he said.