These fungi are typically soil organisms and generally distributed worldwide [6]. However, there are species that do appear to be geographically restricted, such as Ramichloridium mackenzei, which has only been seen in patients from the Middle East [7]. Exposure is thought to be from inhalation or minor trauma, which may not even be noticed by the patient. Anecdotal reports suggest that smoking may be a risk factor in patients who are immunodeficient [8]. Surveys of outdoor air for fungal spores routinely observe dematiaceous fungi [9]. This suggests that most if not all individuals are exposed to them, though they remain uncommon causes of disease. These fungi may also be found to be contaminants in cultures, making the determination of clinical significance problematic. At one institution, only 10 % of positive cultures were associated with clinical disease [10]. A high degree of clinical suspicion as well as correlation with appropriate clinical findings and histopathology is required when interpreting culture results.

Little is known regarding the pathogenic mechanisms by which these fungi cause disease. One of the likely virulence factors is the presence of melanin in the cell wall, which is common to all dematiaceous fungi. It may confer a protective advantage by scavenging free radicals that are produced by phagocytic cells in their oxidative burst that normally kill most organisms [11]. In addition, melanin may bind to hydrolytic enzymes, thereby preventing their action on the plasma membrane [11]. In the yeasts Cryptococcus neoformans and Wangiella dermatitidis, disruption of melanin production leads to markedly reduced virulence in animal models [12, 13]. Melanin has also been associated with decreased susceptibility of fungi to certain antifungals, possibly by binding these drugs [14, 15]. It is interesting to note that almost all allergic diseases and eosinophilia are caused by two genera, Bipolaris and Curvularia, though the virulence factors responsible for eliciting allergic reactions are unclear at present [16].

In contrast to other common mycoses that cause human disease, there are no specific serologic or antigen tests available to detect these fungi in blood or tissue. However, the nonspecific serum 1,3-β-d-glucan test may be positive in certain cases of invasive disease [38], and certain species have been demonstrated to contain the FKS gene responsible for its production [39]. The diagnosis of phaeohyphomycosis currently rests on pathologic examination of clinical specimens and careful gross and microscopic examination of cultures (Fig. 12.1). Hospital laboratories can generally identify the most common genera associated with human disease (Fig. 12.2), though referral to a reference laboratory is often needed to identify unusual species. As many of these are rarely seen in practice, a high degree of clinical suspicion is required when interpreting culture results. Increasingly, molecular techniques such as internal transcribed sequence (ITS) sequencing are being used to definitively identify isolates to the species level and are becoming the standard to distinguish between closely related strains and establish novel species [4].

In tissues, these fungi stain strongly with the Fontana-Masson stain, which is specific for melanin (Fig. 12.3) [3]. This can be helpful in distinguishing these fungi from other species, particularly Aspergillus. In addition, hyphae typically appear more fragmented in tissue than seen with Aspergillus, with irregular septate hyphae and beaded, yeast-like forms [3].

Therapy is not standardized for any of these clinical syndromes, and randomized trials are unlikely given the sporadic nature of cases. Itraconazole, voriconazole, and posaconazole demonstrate the most consistent in vitro activity against this group of fungi, though far more clinical experience has accumulated with itraconazole [40]. Isavuconazole is a novel triazole with good in vitro activity, though it is not yet approved for use [41, 42]. Amphotericin B may be used for severe infections in unstable patients; high doses of lipid formulations may have a role in the treatment of refractory cases or in patients intolerant of standard amphotericin B. However, some species of dematiaceous fungi are resistant to this agent. Once the infection is under control, longer-term therapy with a broad-spectrum oral azole is often reasonable until complete response is achieved, which may require several weeks to months.

Other agents have limited roles in treating these fungi. Ketoconazole is not well tolerated, and fluconazole has poor activity against these fungi in general. Terbinafine and flucytosine have occasionally been used for subcutaneous infections in patients refractory to other therapy. Echinocandins do not appear to be very useful as single agents. Combination therapy is a potentially useful therapeutic strategy for refractory infections, particularly brain abscess and disseminated disease, though it has not been well studied. Suggested therapies for specific infections are summarized in Table 12.1.