Phaeohyphomycosis refers to a large group of heterogenous fungal infections that are pigmented (dematiaceous fungi or melanized fungi) and is commonly associated with immunocompromised patients 1. These brown to black pigmented fungi are distinguished by their ability to deposit melanin in their cell walls, which likely acts as a virulence factor 2. Phaeohyphomycosis, first described by Ajello et al. in 1974, literally means a condition of dark hyphal fungus regardless of the causative organism 3. Virtually, everyone is exposed to dematiaceous fungi (melanized fungi) through inhalation, as they are ubiquitous in the environment, although the development of infection is extremely uncommon. These fungi may produce a range of infections from superficial to subcutaneous to deep (visceral) infection characterized by the presence of dematiaceous hyphal and/or yeast-like cells in tissue. Such deep infections due to dematiaceous fungi are termed phaeohyphomycosis. Invasive disease is rare but remains important due to the ability to cause serious disease in immunocompetent and immunocompromised hosts, unlike other fungal infections such as aspergillosis. A large variety of invasive manifestations can be caused by these organisms, including deep local infections, pulmonary infection, cerebral infection, and disseminated disease, which is associated with high mortality 2. While advances in molecular techniques are promising, they have still not replaced histology and culture as the primary diagnostic tools. Therapy is not standardized and is based primarily on clinical experience from descriptive case reports.

The clinical manifestations of pheohyphomycosis can be divided into four categories 4:

  1. Superficial phaeohyphomycosis, including “black piedra” and “tinea nigra” representing infection of superficial layers of skin;
  2. Cutaneous and corneal phaeohyphomycosis, which includes dermatomycosis, onychomycosis and mycotic keratitis;
  3. Subcutaneous phaeohyphomycosis comprising of cystic lesions which usually follow after a traumatic event;
  4. Systemic or invasive phaeohyphomycosis, in which there is dissemination to other organs; this form occurs in immunocompromised patients and organs commonly involved include lungs, brain, paranasal sinuses and rarely, the skin 5.

Although phaeohyphomycosis is uncommon, the incidence of phaeohyphomycosis and the diversity of causative species may be increasing, especially among severely immunocompromised patients 6. A review of the medical literature identified disseminated phaeohyphomycosis as an emerging, frequently lethal mycosis in patients with immune dysfunction 6. However, the full spectrum of diseases caused by dematiaceous molds in immunocompromised patients with cancer remains incompletely characterized, consisting mostly of case reports and small case series 7. Furthermore, the significance of recovering dematiaceous molds from clinical specimens remains unknown, given that these fungi are frequent colonizers 8 and consistent definitions of invasive phaeohyphomycosis are lacking 9.

Subcutaneous phaeohyphomycosis

Subcutaneous phaeohyphomycosis is a rare dematiaceous fungal infection, however, the number of cases appears to be increasing in recent years as the number of immunocompromised patients also have increased 10. However, immunocompromised state is not a necessary prerequisite for phaeohyphomycosis. Infection usually occurs through traumatic inoculation of the skin and subcutaneous tissue 11 with contaminated matter, with majority of lesions occurring on the feet and legs of outdoor workers. The age of patients ranges from 3 to 60 years. Males are more commonly affected because of their outdoor occupation. Subcutaneous phaeohyphomycosis is more common in tropical and subtropical climates.

The most common etiological agents of subcutaneous phaeohyphomycosis are Exophiala jeanselmei followed by Exophiala dermatitidis 12. The genus Exophiala is widely distributed in the environment and may cause infections in both immunocompromised (human immunodeficiency virus patients, transplant recipients, debilitating chronic diseases, diabetes, and immunosuppressive therapy) and rarely, in immunocompetent persons. Exophiala jeanselmei usually causes mild cutaneous and subcutaneous infections which are often localized and solitary (phaeohypomycotic cyst) 13. Even in severely immunosuppressed patients Exophiala infection often tends to stay localized 14.

Common clinical presentation is solitary subcutaneous cyst or abscess, firm to fluctuant, usually sparing the overlying skin. The common site of involvement is upper and lower limbs over the fingers, wrist, knees, or ankles, and less frequently on the face, neck, and scalp. All dematiaceous fungi are similar in morphology and can be differentiated only by culture.

According to Sharma et al. 15 who reviewed the literature on phaeohyphomycosis, 23 patients with subcutaneous phaeohyphomycosis have been reported from India predominantly involving the extremities and very few cases with dissemination. In a study by Murayama et al. 16, 54 cases of phaeohyphomycosis due to Exophiala jeanselmei were reviewed, however, they failed to identify any underlying disease in 31 cases.

A case report highlights the fact that any subcutaneous soft swellings must also be considered under differential diagnosis for fungal infections as they may be mistaken for lipoma, fibroma, epidermal cyst, or foreign body reaction. Surgical excision of the lesion with or without antifungal agents (itraconazole, ketaconazole, amphotericin B) has been widely used in treatment of subcutaneous phaeohyphomycosis 17. Nevertheless; itraconazole at a dose of 200 mg twice daily provided some respite from surgical management in an individual who was unwilling to tolerate extensive debulking surgery 18.

Figure 1. Subcutaneous phaeohyphomycosis

subcutaneous phaeohyphomycosis

Footnote: 8 × 10 cm confluent nodular swelling over the dorsum of the hand with multiple cystic swellings over the feet. All the lesions were excised. Surgical excision of lesions showed no relapse even after 6 months without any antifungal therapy. Patient is still under follow-up.

[Source 19 ]

Phaeohyphomycosis causes

Phaeohyphomycosis belongs to a heterogeneous group of fungal infections, originally described by Ajello and colleagues 20 as mycoses, whose etiologic agents develop in host tissue as dark-walled, septate mycelial elements. The dematiaceous fungi that cause phaeohyphomycosis are ubiquitous inhabitants of the soil and encompass >100 species and 60 genera 7. The most commonly incriminated dematiaceous fungi are Exophiala, Alternaria, Bipolaris, Wangiella, and Curvularia 21. Depending on the immunologic status of the host and the route of infection (cutaneous inoculation or inhalation), these organisms cause a wide spectrum of diseases 22, including allergic diseases (such as allergic bronchopulmonary mycosis and chronic allergic sinusitis), skin and subcutaneous tissue infections, keratitis, invasive sinopulmonary infection, brain abscess, and disseminated infection 23.

Phaeohyphomycosis symptoms

Phaeohyphomycosis is an infection by dematiaceous fungi, which are a large fungal group containing many genera and species, with over 100 molds known to cause infection in humans. These infections are uncommon, life-threatening, and occur in various immunocompromised states. With this wide variety of organisms, the manifestations of infection are also broad and range from fungal keratitis to invasive or disseminated disease.

Phaeohyphomycosis is broadly classified as a deep systemic, subcutaneous, cutaneous, corneal, or superficial mycosis on the basis of the infection site. Subcutaneous infections occur primarily on the extremities, such as the fingers, wrists, knees, or ankles. This may be because these sites are easily exposed due to trauma and wounds and are contaminated by soil, plants, or decomposing wood material, which leads to direct fungal inoculation. Initial manifestations of subcutaneous lesions are often swollen cysts, which are filled with pus and granuloma at the site of probable trauma. These lesions should be differentiated from fibroma, lipoma, sebaceous cysts, and other disorders 12. On histopathologic examination, an abscess surrounded by connective tissue and suppurative granulomatous inflammation was observed 24. As the number of immunocompromised patients (solid-organ transplant recipients, patients with hematologic malignancies, and patients receiving corticosteroids) has increased, so has the number of phaeohyphomycosis reports 9. Human hosts with phaeohyphomycosis are usually HIV co-infected, solid organ transplant recipients or cancer patients, as well as those who are iatrogenically inoculated with the fungi. However, the immunocompromised state is not a necessary condition for phaeohyphomycosis. Phaeohyphomycosis has also been reported in healthy patients, patients who have never received immunosuppressive drug treatment, and those testing negative for diabetes mellitus and HIV infections 25.

Phaeohyphomycosis diagnosis

The diagnosis of phaeohyphomycosis can be difficult because dematiaceous fungi are commonly soil inhabitants and are often considered contaminants when identified in culture. No molecular techniques are presently available to rapidly and reliably identify these fungi to even the genus level 26. It requires strong clinical suspicion and invasive procedures for diagnosis.

Phaeohyphomycosis treatment

There are many treatment challenges with phaeohyphomycosis infections, with strategies usually requiring both a surgical and systemic antifungal component. Polyenes, flucytosine, amphotericin B, itraconazole, voriconazole, echinocandins, terbinafine, and azoles have all been used for therapy with many instances requiring combination of multiple classes of antifungal agents 27. Aggressive therapy is needed specially in cases of brain abscess.

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