A 10-year-old immunocompetent boy presented with multiple, verrucous, disseminated pheohyphomycotic lesions caused by Exophiala spinifera. The patient was not responsive to combination antifungal therapy (itraconazole, terbinafine, fluconazole) and cryotherapy. As antifungal susceptibility is known to be variable for Exophiala spinifera, in vitro sensitivity testing is recommended before medical treatment. This article reviews, in brief, all cases documented so far in the English literature.
Pheohyphomycosis, caused by Exophiala spinifera, a dematiaceous fungus, is an uncommon infection with cutaneous, subcutaneous, and systemic involvement that characteristically forms distinct brown to olivaceous velvety colonies and spine-like annellides on culture.1 Treatment is not well defined. It is often empirical and relies on systemic antifungals and/or complete surgical resection. Here, we report a child with pheohyphomycosis, and discuss the salient clinical features and treatment outcomes in comparison with previously reported cases.
A 10-year-old boy presented with multiple, red, raised, intensely itchy lesions over the face, legs, arms, and upper back of 2 years’ duration. Initially, multiple, pea-sized lesions appeared on the legs, later spreading to other body parts and increasing in size and number. Meanwhile, the leg lesions became verrucous, and a few also ulcerated, discharging pus and blood intermittently. There was no history of trauma, anorexia, arthralgia, bone pains, weight loss, or systemic complaints. The child was not immunized, and there was no history of immunosuppressive drug intake, surgery, or blood transfusion.
Examination revealed a 10-year-old boy weighing 23 kg, with adequate nutrition for his age. He had multiple, bilateral, nontender, discrete, cervical, axillary, and inguinal lymph nodes, 0.5–1 cm in diameter. Cutaneous examination revealed multiple, verrucous plaques and nodules over the legs, upper back, arms, and face. Most plaques over the legs were 3 × 4 cm in size, coalescing, with an ulcerated surface and a rim of hyperpigmentation. Many satellite nodular lesions were present around the plaques. Facial plaques and nodules involved the left cheek and right upper eyelid and eyebrow predominantly, without overlying ulceration (Fig. 1). Systemic examination, including musculoskeletal, neurologic and ophthalmic, revealed no abnormality. His hemoglobin was 14.4 g% with normal total and differential leukocyte count and erythrocyte sedimentation rate. Blood biochemistry, urine examination, and X-rays of the chest, legs including the ankle, knee joints, and skull were normal. Serology for syphilis and enzyme-linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) were negative. Provisional diagnoses of multifocal lupus vulgaris (hypertrophic variant), deep cutaneous mycosis, and cutaneous leishmaniasis (Old World) were considered. Direct smear examination of the tissue in 10% KOH revealed dark, thick-walled, globose, dematiaceous, budding yeast/fungal cells in chains. A skin biopsy from the leg lesion was subjected to histologic examination, culture in Lowenstein Jensen medium for Mycobacterium tuberculosis and atypical mycobacteria, culture on blood agar for bacteria, and tissue culture on Sabouraud dextrose agar medium with and without chloramphenicol and cycloheximide at 30 °C.
Hematoxylin and eosin-stained sections of the lesion biopsy revealed pseudocarcinomatous hyperplasia of the epidermis with fungal spores in the stratum corneum. In the dermis, there were foci of a granulomatous inflammatory infiltrate comprising histiocytes, eosinophils, and a few polymorphs (Fig. 2). Dematiaceous fungi were interspersed amidst this infiltrate, suggesting deep cutaneous mycosis. Cultures for bacterial pathogens and mycobacteria were negative. Tissue culture on Sabouraud dextrose agar medium grew yeast-like, moist, brown–olive green–black colonies at 2 weeks. These eventually became velvety, with short aerial gray hyphae and black pigmentation on the reverse side (Fig. 3). Lactophenol cotton blue mount revealed septate, tan-brown, pigmented, branched hyphae bearing conidiogenous cells (annellides). Annellides were long and rocket shaped. Conidiophores arose from the vegetative hyphae and were septate, and formed distinct spine-like annellated tips (Fig. 4). Ellipsoidal conidia (1–3 × 3–6 µm) aggregated in masses and appeared to slide down the conidiophores. Based on the above characteristics, the isolate was identified as E. spinifera.2
The patient was started on oral itraconazole 100 mg daily and fluconazole 100 mg once a week, together with daily antihistamines. The lesions on the legs and arms were treated with liquid nitrogen cryotherapy at 2-weekly intervals. Initially, there was a 25% decrease in the size of the lesions, but new lesions continued to appear, associated with intractable pruritus. Three months later, as the patient refused parenteral therapy, weekly fluconazole was replaced by terbinafine 125 mg once daily. With this regimen, after 4 months, there was minimal reduction in the pre-existing lesions, with the continued appearance of new lesions, and the patient was lost to follow-up.
Dematiaceous fungi are a group of pigmented, fungal forms found in the environment, and include genera such as Exophiala, Cladosporium, Phialophora, Wangiella, and Fonsecaea. E. spinifera was described in 1968 as Phialophora spinifera, but was subsequently reclassified by McGinnis3 into the genus Exophiala. The fungus is reported to be a well-established etiologic agent of both pheohyphomycosis and chromoblastomycosis. As a disease entity, pheohyphomycosis encompasses all cutaneous, subcutaneous, and systemic infections of humans and lower animals in which the tissue form of the etiologic fungus exists, primarily as nonorganized, septate, dematiaceous mycelia. This is in contrast with classical chromomycosis, in which the tissue form is characterized by muriform, thick-walled, pigmented cells, generally known as sclerotic bodies. Clinically, it is a chronic disease localized to cutaneous and subcutaneous tissue that presents characteristically as subcutaneous abscess/abscesses with the slow development of a purulent center, plaques, or nodules.4,5 In reality, both pheohyphomycosis and chromoblastomycosis represent two extremes of a continuum of infection based on the dynamic interaction between the etiologic agent and the host.
Pheohyphomycosis caused by E. spinifera is a disease of rare occurrence, and only 10 human cases have been reported in the English literature so far from different geographic regions of the world (Table 1). The first case of human infection was described in a 7-year-old boy from northern India, and was originally referred to as chromoblastomycosis caused by Hormodendrum dermatidis by the authors.5 On re-examination of the cultures in 1977 by De Hoog14, it was reclassified in retrospect as E. spinifera. Recently, concurrent double infection of the skin in the form of pheohyphomycosis and nocardiosis has been reported in an 85-year-old Japanese woman, who was on immunosuppressive therapy for idiopathic thrombocytopenic purpura.13 Subcutaneous abscesses involving the skin, muscle, and bone, associated with bone degeneration, have also been described in a patient from Brazil.4 It is noteworthy that pheohyphomycosis caused by E.spinifera presents with single or a few lesions in immunocompromised adults, whereas multiple, widespread verrucous plaques occur in children with no evidence of immunosuppression.5,7,10,12 Whether this is coincidental, or the result of the failure of development of specific immunity in the pediatric age group to limit the infection, needs to be evaluated.
Table 1. Cutaneous infections by Exophiala spinifera
Treatment outcome in pheohyphomycosis has been variable. Excision alone is considered as the treatment of choice for small, early lesions.6,9 Itraconazole has been reported to be the most beneficial drug so far, either alone or following excision of the lesion.6,9,11 Nevertheless, Negroni et al.12 described a case of disseminated pheohyphomycosis in an immunocompetent adult that exhibited only a transient response to itraconazole and flucytosine, and no response to amphotericin-B. These lesions resolved completely with posaconazole, a newer analog of itraconazole.15 The present case showed minimal response to combination antifungal treatment: itraconazole with fluconazole for an initial 3 months, followed by itraconazole, terbinafine, and cryotherapy. In different studies, the in vitro susceptibility of E. spinifera to various antifungal agents has shown that terbinafine, itraconazole, and amphotericin-B are the most active, with the latter having maximum postantifungal effect.16–18 Because of the variation in the antifungal sensitivity pattern of these three drugs, Cermeno-Vivas and Torresrodriguez16 have recommended in vitro susceptibility testing prior to medical treatment. This is further highlighted by the present report where three of these drugs failed to produce substantial cure.
We are grateful to Professor A. Chakraborti, Head of Mycology Division, Department of Microbiology, Postgraduate Institute of Medical Research (PGIMR), Chandigarh, India, for assistance in species identification.