Elsevier

Clinics in Dermatology

Volume 30, Issue 4, July–August 2012, Pages 389-396
Clinics in Dermatology

Eumycetoma

https://doi.org/10.1016/j.clindermatol.2011.09.009Get rights and content

Abstract

Eumycetoma is caused by different fungi. Madurella mycetomatis, Madurella grisae, and Scedosporium apiospermum are the most common causative agents. This disease is more frequent on the lower extremities but can also be present in other areas. The diagnosis is made by direct microscopic examination and histologic study, which should show hyphae and vesicles characteristic of the fungi. Etiologic identification of the species of the fungus is sometimes difficult by culture and biopsy specimen; in these cases, molecular techniques can help to identify the infecting organism. Treatment has been with amphotericin B, which is now seldom used due to its side effects and limited success. The best therapeutic choice is surgical removal of the lesion, followed by medical treatment. This includes antifungals such as the azoles, ketoconazole and itraconazole; in resistant cases, posaconazole and voriconazole are currently recommended. In particular, the combination of terbinafine and itraconazole can elicit a good result in some cases.

Introduction

Mycetoma is an infectious inflammatory disease that affects the skin and can also affect the fascia, tendons, muscles, and bones. It can be caused by bacteria, which are called actinomycetomas, and by fungi, which are called eumycetomas. For prognosis, an adequate clinical differentiation, mycologic corroboration, and additional radiographic studies are essential, because unlike eumycetoma, actinomycetomas require different specific medical treatment.

The term mycetoma is derived from the Greek mykes (fungus) and oma (tumor). In India, the Atharva Veda mentions mycetoma as pada valmikan, meaning anthill foot.1 John Gill first described the disease in 1842 in Madras, India, and called it “Madura foot,” because many patients were from this area. Van Dyke Carter coined the name mycetoma, a term still used to define the disease.2

Along with sporotrichosis, mycetoma is the most common subcutaneous mycosis. Its distribution is global and predominantly in countries with tropical and subtropical climates between the Tropics of Cancer and Capricorn. Actinomycetic mycetomas are more common in Central and South America, and eumycetoma in Africa and India,3 without being exclusive to one area or another. It can also be found in other temperate countries, such as those located in the Mediterranean, including North Africa, Greece, and Italy, as well as the Caribbean Islands, extending to Argentina.4 Cases in travelers who visited endemic areas have been reported.5, 6 Some agents, such as Pseudoallescheria boydii, have been identified as common etiologic agents of eumycetoma in North America.6, 7, 8 This fungus affects men more than women, with a ratio of 4:1, probably due to the greater exposure of men in farm labor. This disease is rare in childhood, although in some countries, such as Sudan, a significant number of affected children have been reported.9

The most important factors in the development of mycetoma are inoculum size, the host's immune response, and hormonal involvement, both in the case of actinomycetomas as well as eumycetomas, which could explain the low prevalence in children.10, 11 The pathogenic role of immunity in mycetoma is not clear. Many individuals in endemic areas have antibodies against Madurella mycetomatis, but the percentage of those affected is comparatively low. This is attributed to a failure of neutrophil function in patients who develop the disease.12 It predominantly affects humans but also has been reported in other species such as horses, dogs, and buffalo.13

At least 30 species of fungi are associated with human eumycetoma.14 The etiologic agents of eumycetoma, depending upon the type of grain, are classified into those that produce black grains and those that produce white or grayish grains. The most important are15:

  • Eumycetoma caused by black fungi or phaeohyphomycetes: Madurella mycetomatis, M grisea, Leptosphaeria senegalensis, Leptosphaeria tompkinsii, Pyrenochaeta romeroi, Pyrenochaeta mackinonii, Cladophialophora bantiana, Cladophialophora mycetomatis (sp nova), Curvularia lunata, Curvularia geniculata, Exophiala jeanselmei, Phialophora verrucosa.

  • Eumycetomas caused by whitish fungi (hyalohyphomycetes): Pseudoallescheria boydii (Scedosporium apiospermum), Acremonium falciform kiliense, Acremonium recifei, Neotestudina rosatii, Fusarium moniliforme, Fusarium solani, Aspergillus nidulans, Aspergillus flavus, Cylindrocarpon cyanescens, and Dermatophytes (Trichophyton rubrum, Microsporum audouinii, Microsporum canis).

More than 90% of eumycetomas reported worldwide are caused by only four agents: M mycetomatis, M grisea, P boydii, and L senegalensis.16 Depending on their geographic location, some of these fungi are reported with greater frequency in certain regions; for example, Acremonium spp and M grisea are common in South America, and M mycetomatis has the most extensive distribution worldwide, predominantly in India and Africa, and in regions like Sudan, it is responsible for up to 70% of the diagnosed cases of mycetoma.17, 18

The percentage of eumycetomas in countries like Mexico is about 2%. In the area of the southern Pacific coast that includes the states of Guerrero and Oaxaca, however, its frequency exceeds 9%. This may be due to the characteristics of the region.19

The disease commonly begins with the traumatic introduction of the infectious agent through the skin with acacia thorns, splinters, or other contaminated objects. Soil is the natural reservoir of most eumycetoma agents from which M mycetomatis, M grisea, P boydii, and N rosati have been more frequently isolated.20, 21 A history of trauma with an object contaminated with infectious agents is common.22, 23, 24

At times, the area of injury may go unnoticed. Initially, a nodular or granulomatous lesion on which a sinus tract forms is observed. The infection can spread from the inoculation site to muscle and bone, especially spongy bone, such as those located in the ankle, wrist, and vertebrae, with which there is a special tropism. Cavities, known as geodes (for their similarity to the mineral rock formations), develop. The evolution of the disease is slow, and factors such as pregnancy and immunosuppressive states may accelerate its spread. Multiple inoculations are rare.

Topographically, the fungi mainly affect the feet (80%), legs (7%), and hands (6%).25 In Mexico, the back has been reported as the second most common site.26 There are a few reports of infection of the skull,27 abdomen, and chest, which may or may not be associated with immunosuppression.28

Mycetomas present with tumefaction of the affected area that gradually becomes deformed with the presence of nodules. These form abscesses and fistulas that drain a mucopurulent exudate in which fungal colonies in the form of grains are found. They sometimes invade bones, causing osteomyelitis. The grains can be observed with the naked eye or microscopically as in the case of M grisea, M mycetomatis (Figure 1), and P boydii. The morphologic characteristics and color of the grains contribute to their identification.

The dermatosis is usually unilateral, and a presentation in more than one location in the same patient is rare.29 Dissemination to the pelvic organs through the lymphatic pathway of the lower limbs has been reported.30 Cases of disseminated eumycetoma occur in infections with a long evolution.

Eumycetoma differ from actinomycetomas by the agents that cause them—true fungi in the former and actinomycetic aerobic bacteria in the latter—and by some clinical differences: eumycetoma have less inflammation and lesions are less aggressive and with fewer fistulas (Figure 2), they tend to be encapsulated, and invasion of bone structures is slower than in those caused by actinomycetes.31 These characteristics allow surgical treatment without amputation. In selected cases the best therapeutic choice is surgical removal of the lesion associated to medical treatment.32

Some untreated eumycetomas can eventually become intensely deforming (Figure 3). Despite the severity of the clinical manifestations, the symptoms are usually discrete or absent. There may be pain before the rupture of the abscesses that develop fistulas,33 and Staphylococcus aureus infection can also develop.34 The prognosis varies according to the causative agent, the depth of the infection, the extent and involvement of bone structures, and the resistance to antifungals.8, 35

The differential diagnosis of eumycetoma is made with diverse pathologies. In early lesions, they can be confused with foreign body granulomas, various benign and malignant soft tissue neoplasias,36 and cystic lesions. Nonfistular lesions should be differentiated from sporotrichosis, chromomycosis, or conidiobolomycosis. Other diagnoses to consider are leishmaniasis, cutaneous tuberculosis, and cellulitis.16 Although the clinical characteristics are critical, laboratory studies are needed to establish the etiologic diagnosis.

Histologically, abscesses surrounded by inflammation, pseudoepitheliomatous hyperplasia, abundant granulation, and fibrous tissue are observed. The grains can be seen in the center of the abscesses. Special stains—Grocott, periodic acid Schiff, and hematoxylin and eosin—help to distinguish the different varieties of grain. An alternative that facilitates obtaining samples is fine-needle aspiration for cytologic diagnosis.37 This procedure is quick and easy to perform, readily providing material for culture and direct mycologic study, histopathology, and molecular techniques for the specific identification of the causative agent.38, 39, 40, 41

Morphologic methods are used to identify genus and species of eumycetoma, including direct examination, culture, and histopathology.42 Immunologic methods have also been described, including enzyme-linked immunosorbent assay to determine specific antibodies.43 Transmission or scanning electron microscopy has also contributed data to determine the ultrastructure of the grains in the tissues.44 It is not always possible to diagnose the genus and species by studying pathologic specimens because (1) cultures are often contaminated with bacteria and are negative, and (2) when the culture is positive, the morphologic structures are often difficult to identify.

For this reason, molecular diagnostic techniques, such as polymerase chain reaction (PCR) in its various forms have been introduced, including PCR restriction fragment length polymorphism [RFLP], real-time PCR, and DNA sequencing.45, 46 These techniques have been used to identify the species of eumycetoma from biopsies of lesions and isolation from the environment (soil and plants), for example, Phaeoacremonium spp,47, 48 as well as black grain–producing species, such as M mycetomatis, M. grisea, E jeanselmei, P romeroi, P. makinnonii, L senegalensis, L tompkinsii, and C lunata.41, 49

Molecular techniques have identified some species of fungi that cause phaeohyphomycosis and hyalohyphomycosis, such as C bantiana50 and P krajdenii,51 which also cause eumycetoma. Etiologic agents of this disease are numerous (Table 1). In this contribution, we describe only those methods of identification based on the morphology of the grains and cultures of the most frequent fungi.52, 53, 54, 55, 56

Examination will show oval black grains, globose or lobulated, 0.5 to 1 mm to 5 mm when two or more come together. Light brown hyphae are 1 to 5 mm in diameter. Microscopically, the grains are reddish-brown.

The hyphae are white and membranous at first; eventually, they turn yellow-brown with a dark pigment that diffuses into the culture medium. It grows at 26°C, with optimal development at 30°C. The cultures present pseudoparenchymatous sclera with polygonal cells. They produce oval or pyriform conidia (3.5-5 μm), originating in simple or branched conidiophores that occasionally develop spherical phialides with microconidia in cornmeal media.

Globose or lobed black grains are 0.5 to 1 mm in diameter; the grains are initially soft and then hard and brittle. A clear center surrounded by brown, pigmented hyphae is observed microscopically.

Growth is slow at temperatures of 26° to 30°C; it is gray-green and grows slowly, and has peripheral folds and short aerial hyphae. It sometimes develops a reddish-brown pigment. Hyphae (1-3 μm) are septated and have a pigmented wall. There is no sporulation, and sometimes, abundant pycnidia and chlamydoconidia (4 to 7 × 3 to 4 μm) are observed.

The yellowish-white, soft, lobed, or globose grains are 1 to 2 mm in diameter. The hyphae (2-5 μm in diameter) are hyaline and flexuous. In the periphery of the grain, they become globose and produce other secondary hyphae (10 to 20 μm).

The colonies are dark gray to grayish brown with a cottony appearance that eventually becomes a lighter color; this fungus is homothallic, producing brown cleistothecia of 100 to 200 μm in diameter. When grown on agar media, cornmeal, or potato dextrose, they present oval or subglobose asci (12-18 and 8-13 μm), which contain eight ascospores. When the wall of the ascus breaks, it releases elliptical and dark ascospores (4-5 and 7-8 μm in diameter).

Soft, white or pale yellow grains with a variable shape formed by masses of vesicular hyaline hyphae become apparent.

The colonies are white, gray, brown, or pale violet, with red-violet pigment on the back. They have elongated phialides with conidia grouped by the production of slime. The three species of Acremonium with terminal or intercalary chlamydoconidia are A kiliense, with unicellular conidia (3-6 and 1-1.6 μm); A recifei, with crescent-celled conidia (4-6 and 1.3-2 μm); and A falciforme with one- to two-cell conidia in a half-moon shape (7-8.5 and 2.7-3.2 μm).

Phaeoacremonium, a genus that is morphologically similar to Acremonium, has been reported as a cause of mycetoma. The morphologic differentiation of Phaeoacremonium is difficult because its only feature is a discrete pigment in its colony growth. Species differentiation is achieved solely by molecular studies.

This involves dark grains that become elongated when they are secreted in pus; in tissues, they become spherules with sinuous bands and clear spaces. They are dark and have a thick wall (5-10 mm in diameter). The hyphae of the central part of the grain are smaller.

The colonies are dark with a tendency to become brown with a yeastlike or membranous aspect and slow growth. In subculture, colonies develop a filamentous aspect with short aerial hyphae. In yeast cultures, conidiogenic cells are born laterally from the hyphae, which are short and annellidic. In primoisolated colonies, phialides are observed that disappear in subcultures. The conidia vary in size, from 1.5 to 3.5 μm in diameter and 5 to 10 μm in length, are elliptical (1-2 × 2-6 μm), and occur successively at the tip of the annellide.

Spherical or tubular black grains (0.5-1.5 mm in diameter) are present, with the center being pale and lacking interstitial material. The hyphae are black on the periphery of the grain.

Dark gray colonies with a clear margin and a cottony appearance are present. They grow at 30°C, producing brown pycnidia (50-150 × 40-300 μm). On the inner wall of the pycnidia conidiophores, which produce hyaline, elliptical conidia (1-1.5 × 2-5 μm) are formed.

Black grains (0.7-1 mm in diameter) with a soft consistency are present and have a darker periphery than the center, with vesicles of 15 to 40 μm. Irregularly shaped sets of hyphae are occasionally observed. The distribution of the hyphae is more erratic than in other grains of eumycetoma. Dark cement that contains vesicles is deposited in the periphery of the grain. The center of the filament is clear because there are no fungal filaments.

The colonies are fast growing, dark brown with a black back that is occasionally pink. In cornmeal agar at 27°C, they produce perithecia (100-300 μm). Asci measure 80 to 100 × 17 to 22 μm and contain eight ascospores. These ascospores have four septa.

Round, oval, or lobed white grains (500-1000 μm) are present, with compact grains having cement in the center and basophilic hyphae.

Growth is slow. It has a yellow ocher color with peripheral folds; in media such as cornmeal, asci with ascospores are produced after 3 weeks. The ascostromas are highly distinguishable because of their dark color. The asci are long, more than 30 μm, and thick-walled, containing eight ascospores that are 10 μm long.

Brown to black grains (0.5-1.5 mm), ovoid, spherical, or irregularly shaped appear. In the periphery, black chlamydoconidia, swollen cells, and deformed mycelium embedded in cement are observed. The center of the grain is vacuolar or lax.

Cottony, black colonies are formed. The conidiophores produce three to five conidia with a puffed and curvilinear center.

Section snippets

Imaging

The various imaging methods help determine the extent of disease and bone involvement.57 An increase in volume of the soft tissues (93%), bone sclerosis (56%), bone cavities-geodes (32%), periosteal reaction (27%), and osteoporosis (19%) are frequently observed.58

Ultrasound imaging is useful in eumycetoma with thick-walled cavities without acoustic resonance.59 This method is inexpensive and relatively simple. The image known as the “dot in circle” is considered a radiographic sign that is

Treatment

Contrary to the therapeutic results observed in actinomycetomas, where medical treatment cures most infections without surgery, combined medical and surgical treatment is the standard to follow in eumycetoma. The antifungals used in the treatment of mycetoma since the 1960s have included amphotericin B, clotrimazole, and griseofulvin. The latter two are no longer used. Amphotericin B has been indicated sporadically, with limited success due to its adverse effects, and its use in this disease is

Conclusions

Eumycetoma is a fungal disease that requires an early, accurate diagnosis and, if possible, with in vitro susceptibility studies of the fungus to various antifungal agents. Medical treatment with imidazoles and terbinafine, combined with a surgical treatment that achieves removal of the infected area, is suggested; if this is not completely accomplished, antifungal treatment should be continued for a longer period of time, during which the therapeutic outcome and the appearance of adverse

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