Continuing Education Activity

Mycetoma is characterized by a progressive and chronic granulomatous infection affecting the skin and subcutaneous tissue. Mycetoma can be classified as "eumycetoma" when it is caused by fungi or "actinomycetoma" when caused by bacteria in the order Actinomycetes. Therefore, eumycetoma is a deep fungal infection of the skin and subcutaneous tissue commonly caused by the filamentous fungi Madurella mycetomatis. Eumycetoma is characterized by a deep granulomatous inflammation, resulting in the formation of grains, which destroy tissues such as muscles, bones, joints, and tendons. Clinical features include painless plaques with hard woody swelling, discharging sinuses, and characteristic granular grains or microcolonies. The World Health Organization (WHO) recognizes mycetoma as a neglected tropical disease, which primarily affects individuals in tropical and subtropical regions who come into direct contact with soil.

The foot is often prone to fungal infections due to exposure to fungi in the soil via skin trauma. This type of infection usually enters through skin damage and causes symptoms in the feet, hands, or legs. Managing eumycetoma poses significant challenges and necessitates a prolonged treatment regimen that often combines systemic antifungal therapy for an extended duration with surgical interventions. Neglected infections may lead to severe tissue destruction, underscoring the medical significance and treatment complexities associated with eumycetoma. This activity provides a comprehensive review of the evaluation, diagnosis, and treatment of eumycetoma, highlighting the pivotal role of the interprofessional healthcare team in facilitating early diagnosis and treatment for patients affected by this condition.

Objectives:

• Identify the characteristic clinical features of eumycetoma, including painless plaques, hard woody swelling, and discharging sinuses.

• Screen individuals in endemic regions for signs and symptoms of eumycetoma, especially those with a history of barefoot walking and soil exposure.

• Select appropriate antifungal agents for systemic antifungal therapy and dosage regimens tailored to the severity and duration of eumycetoma infection.

• Collaborate with interprofessional healthcare teams, including dermatologists, infectious disease specialists, and surgeons, to optimize patient care and outcomes and ensure comprehensive monitoring for relapse or complications.

Introduction

Mycetoma is a progressive chronic granulomatous infection that affects the skin and subcutaneous tissue.[1] Mycetoma can be classified as "eumycetoma" when it is caused by fungi or "actinomycetoma" when caused by bacteria in the order Actinomycetes. Eumycetoma is, therefore, a deep fungal infection of the skin and subcutaneous tissue caused by filamentous fungi.[2] Morphologically and histologically, eumycetoma is characterized by a deep fungal infection that induces deep granulomatous inflammation and results in the formation of grains, which destroys deep tissues, muscles, bones, joints, and tendons.[3][4][5]

The World Health Organization (WHO) recognizes mycetoma as a neglected tropical disease with a significant disease burden, which primarily affects individuals in tropical and subtropical regions who come into direct contact with soil. The foot is particularly the most common site of fungal infections, as it frequently comes into contact with fungi in the soil through skin trauma due to the natural exposure of soil-borne fungi that breach the skin.[6][7] In less frequent instances, other areas, such as the legs or hands, may also be affected, as these infections usually enter through skin damage and, in rare cases, spread via hematogenous dissemination to other sites.[8][9][10]

The most common filamentous fungi causing an eumycetoma is Madurella mycetomatis.[11] These organisms are found in the soil and implanted in the skin after minor trauma.[12] Slow progressive subcutaneous swelling develops, followed by the formation of multiple nodules that evolve into suppurative lesions with numerous draining sinus tracts, from which colonies of causative organisms are discharged.[13] Managing eumycetoma poses significant challenges and necessitates a prolonged treatment regimen that often combines systemic antifungal therapy for an extended duration (6 months or more) with surgical interventions.[14] Neglected infections may lead to severe tissue destruction, underscoring the medical significance and treatment complexities associated with eumycetoma.[15][16] In endemic areas, eumycetomas lead to socio-economic consequences involving affected patients and their families.

Etiology

The most prevalent causative agent of eumycetoma worldwide is M mycetomatis. Etiologic agents of eumycetoma can be classified based on the type of grain they produce, typically categorized as black, white or pale unstained, or yellow-to-yellow-brown grains. Some of the important causes of the disease are mentioned below.

• Dark and black grains: Dark and black grains are primarily associated with pathogens such as M mycetomatis, Trematosphaeria grisea (formerly M grisea), Exophiala jeanselmei, Medicopsis romeroi (formerly Pyrenochaeta romeroi), Falciformispora senegalensis (formerly Leptosphaeria senegalensis), F thompkinsii, and Curvularia lunata.

• White or pale unstained grains: White or pale unstained grains are commonly associated with pathogens such as Acremonium spp, Fusarium spp, Neotestudina rosatii, Aspergillus nidulans, and A flavus, as well as Microsporum ferrugineum, M audouinii, and M langeronii. In addition, Scedosporium apiospermum and S boydii (formerly Pseudallescheria boydii) are also linked to this type of grain.

• Yellow-brown grains: Yellow-brown grains are typically attributed to pathogens such as Nocardia brasiliensis, N otitidiscaviarum (formerly N caviae), Actinomadura madurae, and Streptomyces somaliensis.

• Yellow grains: Yellow grains can be associated with Pleurostomophora ochrac.[17]

Many of these organisms are endemic to tropical areas; however, cases are also reported in the United States and other countries.[1]

Epidemiology

Mycetoma was included in the WHO list of neglected tropical diseases in 2016. Populations in tropical and subtropical countries, such as India, and West African countries, such as Senegal and Sierra Leone, who often walk barefoot, are particularly affected.[18] The regions where mycetomas are endemic are commonly referred to as the "Trans-African Belt" or "mycetoma belt." This belt extends between 15° and 30° north latitude, covering geographical areas from Sudan to Senegal.[17] Primary mycetomas are rare in developed nations and typically observed in individuals migrating from endemic countries.

Eumycetomas are predominantly observed in adult men at a ratio of 4:1 or higher, likely due to the mode of disease transmission.[19] Individuals with increased exposure to soil and a history of prior trauma to their feet or other soil-exposed areas, including farmers, homemakers, and breeders, are at higher risk of developing this condition. However, only 20% of individuals recalled experiencing a preceding traumatic event, typically involving injuries caused by splinters, thorns, or other activities related to animal bites or physical exertion.[20]

Pathophysiology

Classically, the disease course begins with fungi entering through broken skin, which are naturally found in soil, water, or plants.[21] These organisms then start to form a clonal population, leading to the development of grains.[22] Subsequently, their pathogenicity is likely based on their ability to evade the host immune system and induce changes in the host response. Interleukins (IL), such as IL-35 and IL-37, are associated with the lesion size of eumycetoma, playing a role in dampening the immune system. These ILs are negatively correlated with the levels of IL-1β and IL-12 in eumycetoma infection, thereby impacting disease progression.[23] 

Low levels of interferon-γ and increased IL-10 have also been associated with harmful disease progression. Fungal elements, such as melanin and carotene, along with the ability of yeast to survive after a host neutrophilic and macrophage response, are likely involved in shielding the organism from complete degradation and subsequent granuloma formation.[24]

Histopathology

Key histopathological features of eumycetoma include the formation of epithelioid granulomas containing microcolonies and grains,[2] which are conglomerates of fungal hyphae. A foreign body reaction to fungal elements in eumycetomas leads to granuloma formation characterized by epithelioid cell hyperplasia and multinucleated giant cells.[25] Histological examinations of eumycetomas typically involve hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. Additionally, a methenamine silver stain may be considered.[26] This microscopic image provides a detailed view of Aspergillus niger, showcasing its characteristic features such as wide, branching septate hyphae and well-formed conidial heads (see Image. Histopathological View of Aspergillus niger).[17]

History and Physical

Eumycetoma primarily manifests on the feet (followed by hands and legs) and presents as painless plaques with hard woody swelling, discharging sinuses, and characteristic granular grains or microcolonies, representing key clinical features.[20] Communicating sinuses and fistulae actively discharge purulent material and granules, varying in color from white to yellow to black. Scarring and hyperpigmentation are commonly observed in the surrounding skin. Eumycetomas are endemic among barefoot-walking populations in Africa and Southeast Asia.[17] Therefore, the classic triad of eumycetoma includes tumor growth, sinus tracts, and discharge with grains.[27] Following inoculation of the causative agent, subcutaneous mycosis gradually develops over months to years, indicating a chronic infection.[28] 

Evaluation

Clinical evaluation may be sufficient for diagnosis, especially in low-resource settings, based on the triad of diagnostic findings (tumor, sinus tracts, and discharge with grains). However, additional testing may be necessary, including culture, which can take up to 2 months, ultrasonography, or fine needle aspiration, which is the preferred method.[20][29] Advanced imaging studies may not be readily available, as this condition often presents in low-resource settings.

Punch Biopsy and Histopathological Examination of Skin Tissue

The most specific test for diagnosing eumycetoma involves examining grains or granules from discharge, both visually and microscopically.[30] This examination can be conducted on spontaneously drained material or material manually expressed from the sinus, although there is a risk of sample contamination with expressed material.[2] In many cases, a punch biopsy may not be necessary. However, a deep punch biopsy can be a diagnostic tool if drainage material cannot be expressed or examined. Grains or microcolonies are typically found in the subcutaneous tissue, necessitating a deep punch or excisional biopsy to access the morphological structures of eumycetomas. H&E staining of tissue sections and fungal staining techniques such as PAS provides detailed visualization of fungal grains.[31] 

Imaging and Additional Diagnostic Modalities  

The effective treatment of eumycetoma hinges upon accurately identifying the causative agent and assessing the extent of the disease. Imaging may be necessary to determine the disease burden, utilizing techniques such as x-ray, ultrasonography, computed tomography (CT) scans, and magnetic resonance imaging (MRI).[32] CT scans are particularly advantageous over traditional radiography. MRI may be employed when there are concerns regarding soft tissue or bone involvement, with a characteristic finding known as the "dot-in-circle" sign.[33][34][35] Surgical biopsy, histopathological examination, and fungal tissue cultures are crucial in identifying the organism. Additionally, molecular techniques such as species-specific polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and counter immunoelectrophoresis may be utilized for further characterization.

Treatment / Management

The treatment of eumycetoma remains challenging, as no definitive treatment protocol guidelines have been established. Current treatment strategies are primarily derived from published case reports and case series. Typically, treatment involves a combination of antifungal therapies and surgical procedures. Initially, preoperative antifungal therapy is administered for a duration of 6 months, followed by surgical procedures aimed at debulking and reducing the disease burden, succeeded by an additional 6 months of antifungal therapy.[36] However, some reported cases have shown improvement with medical therapy alone.[37][38][39] Notably, in many low-resource settings, medical treatment may be the only feasible option, as surgical debridement may not be readily available.

Antifungal Therapy

Various classes of antifungals have been used to treat eumycetoma, including azoles, amphotericin B, and terbinafine.

Azoles: Azole antifungals are considered the "gold standard" for treatment, with itraconazole being the most commonly used.

• Itraconazole is typically administered at a dosage of 400 mg daily, divided into two doses, for a duration of 12 months. Hepatotoxicity is the primary chronic adverse effect associated with itraconazole therapy.[40] Extended treatment duration has been identified as a crucial factor for achieving a higher cure rate, with eumycetoma patients often requiring treatment ranging from 6 months to 3 years.[41]

• Newer azoles, including voriconazole (administered at a dosage of 400 to 600 mg/d) and posaconazole (at a dosage of 800 mg daily), have also been trialed and have demonstrated favorable clinical outcomes.[39][42][43]

Amphotericin B: The toxicity and requirement for hospitalization have significantly restricted the utilization of amphotericin B. Although liposomal amphotericin B has been used in certain cases in endemic regions, its efficacy has been inadequate, and the severe adverse effect of nephrotoxicity limits its application.[36] Intralesional administration of amphotericin B has demonstrated favorable outcomes in select cases with a solitary lesion; however, it is not an efficacious treatment option for multilobulated lesions due to uneven drug diffusion and the risk of dissemination.[44]

Terbinafine: Administration of 500 mg of terbinafine twice daily for 24 to 48 weeks has resulted in significant clinical improvement in 80% of cases.[45]

Surgical Interventions

Authors of one study recommend a stepwise approach, beginning with the initial preoperative treatment of eumycetoma using itraconazole. Antifungal therapy promotes encapsulation of eumycetoma, facilitating better localization and surgical debridement. This approach allows for avoiding comprehensive, extensive, and disfiguring procedures.[17]

Differential Diagnosis

The differential diagnosis should include the following:

• Lobomycosis: This is a chronic cutaneous fungal infection caused by Lacazia loboi endemic to Central and South America. Initially, lesions manifest as papules and advance to keloid-like formations, appearing as smooth nodules predominantly found on the hands, ears, and ankles. In contrast, mycetoma is characterized by sinus or fistula formation with the expulsion of granules.[46][47] 

• Mycobacterium marinum: This is an atypical mycobacterial infection acquired through contact with contaminated swimming pools, lakes, or ocean water and is also known as "fish tank granuloma." Clinically, the infection presents with tender red nodules on the fingers or hands.[48]

• Chromoblastomycosis: This is a subcutaneous fungal infection caused by dematiaceous fungi commonly observed in tropical and subtropical climates. Chromoblastomycosis typically manifests in middle-aged men with crusted lesions affecting the lower extremities.[49]

• Histoplasmosis: This is a fungal infection characterized by umbilicated papules, nodules, or indurated ulcers. Associated lymphadenopathy is commonly observed. Risk factors for systemic involvement include immunosuppressed states.[50]

• Cutaneous tuberculosis: This condition is clinically heterogeneous and presents as non-healing nodules, ulcers, plaques, or draining lymph nodes in patients from endemic areas.[51]

• Additional conditions: Other conditions to consider encompass deep fungal infections, atypical mycobacterial infections, podoconiosis, leishmaniasis, folliculitis, cysts, foreign body granulomas, and botryomycosis.[52][53]

Prognosis

Untreated eumycetoma follows a slow but inevitable progression.[49] In cases where this condition is not promptly recognized, or treatment is unavailable or unaffordable, initially painless eumycetoma can advance to limb destruction and necessitate amputation (see Image. Progressing Eumycetoma with Deep-Tissue Penetration). Studies reviewing multiple cases of eumycetomas have identified several positive prognostic factors, including longer duration of therapy and absence of relapse in patient history. Additionally, mycetomas measuring between 5 and 10 cm or greater than 10 cm, managed with a combination of medical and surgical treatment, are significant predictors of a favorable outcome.[17] Relapse of eumycetoma is common, especially among individuals with a disease duration exceeding 10 years and those with involvement outside of the feet. According to a machine-learning algorithm, individuals with a history of prior surgical excision, a family history of the condition, or employment as non-farmers are at an increased risk of recurrence.[54][55] 

Complications

If left untreated, the infection can spread along fascial planes and affect muscle and bone, resulting in complications such as osteomyelitis or extension into deeper structures, which can render the organism more resistant to treatment (see Image. Advanced-Stage Eumycetoma With Gangrenous Features).[56][57] Moreover, the condition may cause significant deformities with associated psychosocial consequences.[58][59]

Deterrence and Patient Education

Considering the pathogenesis of this disease, wearing shoes can help prevent injuries that may lead to eumycetoma. Therefore, avoiding walking barefoot in highly endemic areas is advisable whenever possible. Shoes provide protection for the feet while walking or working in environments where exposure to fungal elements in water and soil is likely. Early detection and treatment, before the eumycetoma spreads deeper across fascial planes, can help reduce disabilities associated with eumycetoma and improve outcomes.

Enhancing Healthcare Team Outcomes

Eumycetoma often presents a diagnostic and treatment challenge. The condition arises following traumatic inoculation of filamentous fungi in individuals who walk barefoot in endemic regions. On physical examination, nonhealing, chronic nodules, and sinus tracts are commonly observed on the legs, persisting for many years. The availability of healthcare services in regions where eumycetoma is prevalent significantly influences the speed at which diagnosis and treatment can be initiated.

Patients with eumycetoma require collaboration with an interprofessional healthcare team comprising a dermatologist, an infectious disease specialist, and a surgeon for lesion debulking. Pharmacists are critical in ensuring appropriate dosing of oral antifungals during the initial stages of treatment. Dermatopathologists are involved in examining biopsy specimens histopathologically to establish an accurate diagnosis. Additional radiological examinations may be necessary for longstanding, widespread infections. Although definitive guidelines for managing eumycetoma are lacking, treatment regimens are derived from case series and a comprehensive review of current medical literature published in peer-reviewed journals.[17] The outcomes of eumycetoma rely on prompt diagnosis and timely management of the condition; hence, early consultation with interprofessional healthcare specialists is highly recommended.