Disseminated phaeohyphomycosis is an uncommon infection caused by dematiaceous fungi, although the number of case reports about this infection has been increasing in recent years. A total of 72 cases are reviewed. Scedosporium prolificans is by far the most common cause. The presence of melanin in their cell walls may be a virulence factor for these fungi. The primary risk factor is decreased host immunity, although cases in apparently immunocompetent patients have been reported. Eosinophilia was seen in 11% of cases. Endocarditis is mostly reported on bioprosthetic valves, particularly those of porcine origin. The outcome of antifungal therapy remains poor, with an overall mortality rate of 79%. Special precautions taken for immunocompromised patients may help prevent exposure to fungi during the patients' period of greatest risk. The development of newer antifungal agents and combination therapy may hold promise in improving the management of these devastating infections in the future.
The term “phaeohyphomycosis” was introduced by Ajello et al. [1] in 1974 to designate infections caused by dematiaceous or pigmented filamentous fungi that contain melanin in their cell walls. It literally means “condition of fungi with dark hyphae.” “Dematiaceous” has recently come under scrutiny as an improper term for denoting darkly pigmented fungi, because its root comes from a Greek word meaning “bundle,” although the term remains widely used [2]. Phaeohyphomycosis should be distinguished from other specific pathologic conditions such as chromoblastomycosis and mycetoma, which are also caused by dematiaceous fungi. Chromoblastomycosis, which is caused by a small group of fungi that produce characteristic sclerotic bodies in tissue, is usually seen in tropical areas [3]. Mycetoma is a deep-tissue infection, usually of the lower extremities, characterized by the presence of mycotic granules [3]. Several excellent reviews are available that discuss these infections caused by dematiaceous fungi [3–6].
During the past several decades, phaeohyphomycosis has been attributed to >100 species and 60 genera of fungi in a variety of clinical syndromes, ranging from keratitis and solitary subcutaneous nodules to fulminant, rapidly fatal disseminated disease [5]. Most of the species are considered to be opportunistic pathogens, although some may be true pathogens. Almost all cases of widely disseminated infection have occurred in immunosuppressed patients. We review 72 cases of disseminated phaeohyphomycosis in the literature, including a case of infection due to Bipolaris spicifera in a heart transplant recipient from one of our institutions. Because fungal taxonomy is constantly evolving, we have attempted to use the most recent nomenclature available. We recognize that experts may disagree on particular taxonomic issues and future changes are likely.
Methods
Literature search. The MEDLINE database (National Library of Medicine, Bethesda, Maryland) was searched for relevant articles published during the years of 1966–2001; we looked for the terms “phaeohyphomycosis,” “disseminated,” and the genus names for 61 known clinically significant dematiaceous fungi, primarily from a list compiled by Matsumoto et al. [5]. Additional cases were obtained by scanning the reference sections of the articles obtained via MEDLINE. Only English-language articles were included.
Definition. Cases were included if all the following criteria were present: (1) the clinical syndrome was consistent with infection, (2) recovery of the isolate from blood samples or evidence of infection at ⩾2 noncontiguous sites, and (3) mycologic identification was confirmed by means of culture.
Results
A total of 72 cases of disseminated phaeohyphomycosis were studied. These are summarized in table 1. Male patients accounted for 41 (57%) of 72 cases and female patients accounted for 31 (43%) of 72 cases. The mean patient age was 42 years (range, 0–92 years). Seventy-five percent of all cases were reported during the years of 1992–2001.
Microbiology. A total of 28 species of fungi were isolated from the 72 patients with cases (table 2). This list of etiologic agents is not all-inclusive, nor will it necessarily be agreed upon by all mycologists or clinicians. The fungi presented here are those that we think represent the major and adequately documented agents of disseminated phaeohyphomycosis in the English-language literature. Scedosporium prolificans accounted for 30 (42%) of 72 cases, by far the most common species responsible for disseminated disease. Of interest, all of the case reports involving S. prolificans were published within the past 10 years. The next most common species was B. spicifera, which was seen in 6 (8%) of 72 patients, followed by Wangiella dermatitidis, which was seen in 5 (7%) of 72 patients. Twenty species were associated with only 1 case report each, which illustrates how uncommon many of these infections are. Representative photomicrographs of some of the more common agents and an example of a Masson-Fontana stain are shown in figure 1.
Underlying disease and risk factors. Many patients had >1 risk factor (risk factors are detailed in table 3). Some degree of immune dysfunction was associated with disseminated disease in 55 (76%) of 72 patients. Thirty-nine (54%) of 72 patients had a malignancy diagnosed, and 37 (51%) of 72 patients had neutropenia, which was most often related to recent chemotherapy. Seven patients were undergoing bone marrow transplantation, and 6 had received a solid-organ transplant. Three patients were HIV positive, all of whom had AIDS. Almost all cases due to S. prolificans (27 [90%] of 30 cases) were associated with persistent neutropenia. One case was in a premature infant (23 weeks' gestation).
In 17 (24%) of 72 patients, however, no immunodeficiency was apparent. Of these patients, previous cardiac surgery had been performed in 10 (14%) of 69 patients. Nine patients received valve replacements, and all patients but 1 received bioprostheses. There were 5 porcine valve replacements, 1 bovine valve replacement, 1 homograft, and 1 unspecified bioprosthesis. The mean time from surgery to onset of symptoms was 12 months (range, 2–48 months). A total of 7 (10%) of 72 patients had no apparent risk factor or immunodeficiency. In some of these patients, immunologic studies suggested a defect in cell-mediated immunity as measured by T cell stimulation assays, although the significance of this is unclear.
Clinical characteristics. Fever was the most common symptom but was reported in only 55 (76%) of 72 patients. Skin manifestations, including rash and ulcers, were common and were seen in 24 (33%) of 72 patients. Respiratory and CNS complaints were also common, occurring in 22 (31%) of 72 patients. Gastrointestinal symptoms were seen in 12 (17%) of 72 patients. Sepsis was observed in 8 (11%) of 72 patients, 4 of whom were infected with S. prolificans. Marked eosinophilia was observed in 8 cases of infection. Three of these cases were due to Bipolaris species, 2 each were due to Curvularia and Wangiella species, and 1 was due to Lecythophora species. None of these patients had underlying immunodeficiency, although 1 had been taking steroids for several months.
Sites of infection. The most common site of infection was blood, which was reported in 37 (51%) of 72 patients. Blood was the only site of infection in 6 patients. Infection with S. prolificans was associated with positive blood cultures in 24 (80%) of 30 patients. The next most common site of infection was lung, seen in 33 (46%) of 72 patients; this was followed by the heart, in 21 patients (29%); skin in, 19 patients (26%); brain, in 16 patients (22%); and kidney, in 16 patients (22%). Liver, spleen, lymph nodes, bone and joints, and muscle were less commonly reported as sites of infection. The mean number of organs involved was 3 per patient (range, 1–13 organs per patient).
Therapy. The most frequently used drug was amphotericin B, which was administered to 62 (97%) of 64 patients who received antifungal therapy. Lipid formulations of amphotericin B were used in only 7 patients, 3 of whom survived. Itraconazole, ketoconazole, fluconazole, and flucytosine were used infrequently. Combination therapy was used in 19 patients: 5 patients received amphotericin B and flucytosine, 10 patients received amphotericin B and an azole compound, and 4 patients received all 3 agents. In 10 patients, therapy with amphotericin B was followed by therapy with an azole. Recombinant colony-stimulating factors were provided to 5 patients. One patient received leukocyte transfusions. Surgery was performed in 10 patients; usually, the surgery was valve replacement for treatment of fungal endocarditis.
Outcome. The overall mortality was 79% (57 of 72 patients died). In patients with preexisting immunodeficiency, the mortality rate was 84% (46 of 55 patients died), compared with immunocompetent patients, for whom the mortality rate was 65% (11 of 17 patients died; P = .09). Recovery from neutropenia was considered critical in cases of S. prolificans infection, for which the mortality rate was essentially 100% in patients with persistent neutropenia. What is most notable is the lack of response to amphotericin B in many of the patients: only 14 (23%) of 62 patients who were treated with amphotericin B survived. Although multiple antifungal agents were often used, no single drug was associated with improved outcome. The use of combination therapy did not improve the mortality rate: 13 (72%) of 18 patients who received combination therapy died. Of those treated with amphotericin B and an azole, 11 (79%) of 14 died, although the survival of 1 patient was associated with recovery from neutropenia. The use of recombinant colony-stimulating factors was not associated with improved outcomes, although their use was reported in only 5 patients. All 8 patients who received no antifungal therapy died. Of these patients, 5 had positive cultures at postmortem examination, and 3 had positive cultures before death that had not been considered significant at the time.
Geographic distribution. Agents of phaeohyphomycosis are found worldwide and are predominantly organisms from the soil. However, the majority of patients were from North America (23 cases, primarily from the United States) and Europe (28 cases), possibly reflecting a reporting bias. Nine cases were reported from Australia, 4 cases were reported from the Middle East, and 4 and 3 cases were reported from South America and Asia, respectively. Of interest, 24 (80%) of 30 cases of infection with S. prolificans were reported from Spain or Australia.
Discussion
The number of case reports of disseminated phaeohyphomycosis have been increasing in the past decade. From 1966—the first case we were able to find described in the English-language literature—to 1986, there were 11 cases. Eight of the patients involved had no apparent immunodeficiency. In the past 10 years, 45 cases have been reported, with 41 patients having some type of immunodeficiency, usually chemotherapy-induced neutropenia. This suggests that the main reason for the increase in the number of cases of disseminated disease may be iatrogenic immunodeficiency. Although they are still uncommon as causes of disease, more dematiaceous species are continually being added to the list of potential fungal pathogens, although many would consider them to be opportunistic pathogens. Infection may occur when normal barriers are broken (e.g., traumatic inoculation or during surgery), host defenses are weakened by a medical condition or treatment (e.g., AIDS- or chemotherapy-induced neutropenia), or in patients with chronic sinusitis (allergic fungal sinusitis). Occasionally, certain species of these fungi have been associated with disseminated disease without the above risk factors. Mortality rates are high regardless of the patient's immune status.
The common feature among agents of phaeohyphomycosis is the presence of melanin in their cell walls, which imparts the characteristic dark color to their conidia and hyphae. It is thought to play an important role in the pathogenesis of infections due to these fungi. Melanin is a known virulence factor in fungi and has been extensively studied in Cryptococcus neoformans and Wangiella dermatitidis [62, 63]. Laboratory-derived strains of these fungi that lack melanin demonstrate markedly reduced virulence in mouse models of infection [62]. There are several mechanisms proposed by which melanin may act as a virulence factor. It is believed to confer a protective advantage by scavenging free radicals and hypochlorite that are produced by phagocytic cells in their oxidative burst, which would normally kill most organisms [62, 63]. In addition, it may bind to hydrolytic enzymes, thereby preventing their action on the plasma membrane [62]. Evidence also exists to suggest that melanin is involved in formation of the fungal appressorium, a structure involved in pathogenesis that penetrates host cells [62]. These multiple functions may help explain the pathogenic potential of dematiaceous fungi, even in immunocompetent hosts.
The diagnosis of phaeohyphomycosis can be difficult to make, because these fungi are commonly soil inhabitants and are often considered contaminants when isolated from culture. As with other filamentous fungi, identification by culture requires expert interpretation of colony and microscopic morphology. No molecular techniques are presently available to rapidly and reliably identify these fungi to even the genus level. In tissue, however, they usually have a characteristic appearance of irregularly swollen or toruloid hyphae with yeastlike structures, in contrast to aspergillosis, which typically shows septate, acutely branching, straight-walled hyphae [6]. The melanin-specific Masson-Fontana stain has been used to confirm the presence of dematiaceous hyphae in tissue [6]. However, Kimura and McGinnis [64] reported that other fungi, such as Aspergillus fumigatus and certain members of the Zygomycetes, may also stain positive, although less consistently. Culture and microscopic examination remain the definitive methods to identify these fungi.
What is particularly unusual about these infections is the frequent occurrence of positive blood cultures in more than one-half the cases. S. prolificans is associated with a particularly high rate of fungemia and was responsible for two-thirds of positive blood cultures in this series. In contrast, filamentous fungi, such as Aspergillus species, are rarely isolated from blood samples, even those obtained from patients with disseminated disease. The reason for the high rate of fungemia in patients with disseminated phaeohyphomycosis is unclear, although this may be a consequence of evasion of host defenses caused by the presence of melanin. Additional, unknown virulence factors may also be responsible. In one case of endocarditis due to Bipolaris species, positive blood culture results were considered to have been contaminated and no therapy was provided [41]. Although they are frequently contaminants in the laboratory, agents of phaeohyphomycosis should always be considered seriously when isolated from normally sterile sites in an appropriate clinical setting.
S. prolificans accounted for >40% of cases in this series. It was first described (as Scedosporium inflatum) by Malloch and Salkin [65] in 1984, associated with a case of osteomyelitis. It should be distinguished from S. apiospermum, which has different morphological and physiological characteristics and is not considered to be truly dematiaceous [66]. S. prolificans also has a different teleomorph (Petriella species) than S. apiospermum (Pseudallescheria boydii) [67]. In addition, S. prolificans is generally resistant to all clinically available antifungal agents, whereas S. apiospermum is susceptible to miconazole and the newer azoles, including voriconazole and posaconazole [68–71].
S. prolificans was initially reported to cause bone and joint infections and locally invasive disease in primarily immunocompetent people [43, 72]. Cases of disseminated infection in immunocompromised, usually neutropenic, patients have become more common [14, 18, 31, 37, 73]. The results of blood cultures are frequently positive in these cases. Results of antifungal therapy are dismal without recovery from neutropenia, and mortality rates approach 100%. Of interest, most cases of disseminated infection have been reported from Spain or Australia. S. prolificans has emerged as an important cause of disseminated phaeohyphomycosis, and more effective therapies are clearly needed against this opportunistic pathogen.
Many cases were seen in immunocompetent patients. In 8 of 9 cases of endocarditis, bioprostheses were involved, 5 of which were porcine in origin. We were able to find 6 additional cases of prosthetic valve endocarditis, although without positive blood cultures [74–79]. Four of these were also on bioprosthetic valves, 2 of which were porcine in origin. It is possible that either the valves were contaminated or infected before the operation or that contamination occurred during surgery. It has been suggested that pigs are unusually prone to developing endocarditis [80]. Approximately 10% of pigs in one large study had evidence of endocarditis [81]. If the bioprosthetic valves were not properly sterilized or if the organism was resistant to the standard sterilization procedure, latent foci of infection could have been present that manifested clinically when the valves were implanted in patients. However, given the rarity of this infection, and given that these fungi are commonly found in the environment, it is just as likely that contamination occurred during surgery.
In 8 patients, eosinophilia was a prominent feature of the presentation, and only 1 patient had immunosuppression. Curvularia species and Bipolaris species were responsible for 5 of these cases. Both agents are important causes of allergic fungal sinusitis [82, 83], although none of the patients had obvious sinus involvement. It is unclear what role, if any, the host allergic response had in the pathogenesis of disseminated disease in these patients. Phaeohyphomycosis should be added to the list of infections associated with eosinophilia.
In 7 cases, no risk factor was apparent. Three cases were caused by Curvularia species, 2 were caused by Wangiella species, and 1 each was caused by Bipolaris species and Cladophialophora species. In some of these unusual cases, a variety of pathogen-specific immune defects have been documented, although their exact significance in relation to predisposing to infection remains unclear. It would seem likely that some as-yet-undefined defect in natural immunity is present in these persons that permits the development of widely disseminated disease.
Current therapeutic options for these devastating and frequently fatal infections are limited. Many isolates of dematiaceous fungi are resistant to amphotericin B, which is often considered the “gold standard” for empiric and definitive therapy [84]. Among available agents, itraconazole has the most consistent and potent activity, and an intravenous formulation has recently become available [84, 85]. Terbinafine, although primarily indicated for management of dermatophyte infections and onychomycosis, has been shown to have significant in vitro activity against dematiaceous fungi [86]. There are case reports of successful treatment of cutaneous phaeohyphomycosis with terbinafine as well [87, 88]. Some of the many new antifungal agents being developed hold promise for improving the therapy of these infections in the future. Voriconazole, posaconazole, and ravuconazole are potent new azole derivatives with a generally broad spectrum of activity against dematiaceous fungi [68, 69, 89, 90]. Caspofungin, a recently approved echinocandin antifungal, acts on the fungal cell wall by inhibiting glucan synthase. It does not appear to be as active in vitro, as the azole compounds are, and its role in treating these infections is unclear at present [70].
Combination therapy is another option, although there is limited clinical experience. On the basis of the cases reviewed here, amphotericin B combined with azoles does not appear to improve the outcome of cases of disseminated phaeohyphomycosis. For species such as S. prolificans, no currently approved systemic antifungal agent has significant activity, although voriconazole, an investigational triazole, may have some activity [71]. However, there is promising in vitro data suggesting that the combination of itraconazole and terbinafine is synergistic against S. prolificans [91]. This may be a useful strategy, because both drugs act at different levels of the ergosterol synthetic pathway. Overall clinical experience will ultimately determine which agent or combination of agents is most effective, because it is unlikely that formal clinical trials will be performed, given the rarity of these infections.
Preventive measures may be important to reduce the incidence of these and other mold infections in immunocompromised patients in the future. Given the poor outcome of therapy in patients with immunodeficiency, chemoprophylaxis may be of additional benefit in those persons at highest risk, although this has not been specifically studied with agents of phaeohyphomycosis. Many solid-organ and bone marrow transplant recipients already receive antifungal prophylaxis for Aspergillus species with itraconazole, which has activity against dematiaceous fungi. Because many of the agents of phaeohyphomycosis are common soil inhabitants, they are ubiquitous and difficult to exclude from the hospital environment. Although they have not been studied specifically for prevention of phaeohyphomycoses, air-quality precautions (e.g., positive-pressure isolation rooms and high-efficiency particulate air filters) used to control aspergillosis in some solid-organ and bone marrow transplant units may help control the surroundings of severely immunocompromised patients in the hospital [92].
Disseminated phaeohyphomycosis is an uncommon infection, although its incidence may be increasing, particularly in immunocompromised patients. Aggressive diagnosis and careful interpretation of culture results are important for the treatment of these patients. Newer antifungal agents and therapeutic options will be needed in the future to improve the outcome of these frequently fatal infections.
Acknowledgements
We thank Dr. Joseph McCormack and Dr. Marcio Nucci for providing information regarding the clinical cases.
References
Figures and Tables
a, Scedosporium prolificans (original magnification, ×1500). b, Bipolaris spicifera (original magnification, ×1500). c, Wangiella dermatitidis (original magnification, ×1500). d, Curvularia lunata (original magnification, ×1500). e, Masson-Fontana stain of lung tissue sample obtained from a patient with disseminated phaeohyphomycosis, demonstrating the characteristic appearance of irregularly swollen hyphae with yeastlike structures (original magnification, ×200).
Cases of disseminated phaeohyphomycosis reported in the literature.
Agents of phaeohyphomycosis that caused disseminated infection in humans.
Underlying disease and risk factors in cases of disseminated phaeohyphomycosis.
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