Continuing Education Activity

Eumycetoma is a chronic deep fungal infection of the skin and subcutaneous tissue with protracted disease course if neglected. Endemic regions in tropical and subtropical countries. To avoid the high morbidity from the disease burden associated with this condition, it must be efficiently diagnosed and treated. This activity reviews the evaluation, diagnosis, treatment and highlights the role of early diagnosis and treatment in patients with this condition.

Objectives:

• Summarize the epidemiology of eumycetoma.
• Review the risk factors for developing a eumycetoma.
• Explain the common physical exam findings associated with eumycetoma.
• Summarize the risks associated with initiating long-term oral antifungal therapy along with surgical management and summarize key patient counseling points.

Introduction

Mycetoma is a progressive chronic granulomatous infection of the skin and subcutaneous tissue. The disease can occur due to true fungi, referred to as eumycetoma, or by bacteria, referred to as actinomycetoma. Eumycetoma is, therefore, a deep fungal infection of the skin and subcutaneous tissue caused by filamentous fungi. Morphologically and histologically, eumycetoma is characterized by deep granulomatous inflammation and the formation of grains which lead to the destruction of deep tissue, muscle, bone, joints, and tendons. Mycetoma is a WHO-recognized neglected tropical disease with a significant disease burden. It primarily affects those in tropical and subtropical climates who are in direct contact with soil. The most common site of infection is the foot, followed by hands. Less frequently, other areas may be involved.[1]

The most common organism causing a eumycetoma is Madurella mycteomatis.[2] These organisms are present in soil and are implanted in the skin after minor trauma. Slow progressive subcutaneous swelling then develops, followed by multiple nodules that evolve into suppurative lesions with multiple draining sinus tracts. The sinuses then discharge colonies of causative organisms.[3] 

The treatment course is often protracted, challenging, and consists of systemic antifungal therapy combined with surgical procedures. Severe tissue destruction is an undesired consequence of neglected infections. Eumycetomas are chronic and deep skin infections that carry a medical significance and pose a treatment challenge. In endemic areas, eumycetomas lead to socio-economic consequences involving affected patients, their families.

Etiology

The most common causative agent of eumycetoma worldwide is Madurella mycetomatis. Etiologic agents of eumycetoma can be classified based on the type of grain produced.  Most commonly divided into those producing black grains, white or pale unstained grains, yellow or yellow-brown grains. Some of the important causes are:[4]

• Dark and black grains: Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea), Exophiala jeanselmei, Medicopsis romeroi (formerly known as Pyrenochaeta romeroi), Falciformispora senegalensis (formerly Leptosphaeria senegalensis), Falciformispora thompkinsii, and Curvularia lunata.
• White and pale unstained grains: Acremonium spp., Fusarium spp., Neotestudina rosatii, Aspergillus nidulans, Aspergillus flavus as well as Microsporum ferrugineum, Microsporum audouinii and Microsporum langeronii. Scedosporium apiospermum, Scedosporium boydii (formerly Pseudallescheria boydii) 
• Yellow-brown: Nocardia brasiliensis, Nocardia otitidiscaviarum (formerly Nocardia caviae), Actinomadura madurae, and Streptomyces somaliensis
• Yellow: Pleurostomophora ochrac

Epidemiology

Mycetoma was added to the WHO list of neglected tropical diseases in 2016. Barefoot walking populations of tropical and subtropical countries such as India, West African countries such as Senegal and Sierre Leone are particularly affected.[5] Countries where mycetomas are endemic are considered to be part of the 'Trans- African Belt' or 'mycetoma belt.' This area extends between 15 and 30 degrees north latitude, corresponding to the geographical regions of Sudan and Senegal, respectively.[4] In developed nations, primary mycetomas are rare and more likely to be seen in those migrating from endemic countries.

Histopathology

Key histopathological features of eumycetoma are the formation of epithelioid granulomas with microcolonies and grain. Grains are conglomerates of fungal hyphae. In eumycetomas, foreign body reaction to fungal elements results in granuloma formation with epithelioid cell hyperplasia and multiple nucleus giant cells. In eumycetomas, H&E, PAS staining should be performed. The illustrated figure illustrates Aspergillus niger showing wide, branching septate hyphae and well-formed conidial heads [Figure 1].[4]

History and Physical

Eumycetoma most characteristically occurs on the lower extremities and appears as plaques with hard woody swelling, discharging sinuses, and characteristic granular grains or microcolonies. Communicating sinuses and fistulae actively drain purulent material and granules that vary in color from white to yellow to black. Scarring and hyperpigmentation are noted in the surrounding skin. Eumycetomas are endemic to barefoot walking populations of Africa and Southeast Asia.[4] 

Men between the third and fourth decades of life are most frequently affected. After inoculation of the causative agent, subcutaneous mycosis develops over the course of months to years. If left untreated, the infection can track down fascial planes and involve muscle and bone, leading to complications such as osteomyelitis, making it more resistant to treatment. Less commonly, mycetomas may be found on the hand, leg, or other parts of the body.

Evaluation

Punch Biopsy and Histopathological Examination of Skin Tissue

The most specific test is the examination of grains or granules from discharge both visually and microscopically. This can be performed on spontaneous drainage or manually expressed material from the sinus. A punch biopsy is not necessary in many cases. However, if drainage material cannot be expressed or examined, a deep punch biopsy can be diagnostic. Grains of microcolonies are found in subcutaneous tissue. Therefore a deep punch or excisional biopsy is needed to get access to the morphological structures of eumycetoma. H&E staining of the tissue sections, fungal staining techniques like PAS show details of fungal grains. 

Imaging and Additional Diagnostic Modalities  

Appropriate treatment of eumycetoma starts with precise identification of causative agent and the extent of disease. To determine disease burden, imaging including X-ray, ultrasonography, CT, and MRI may be required.[6] Surgical biopsy, histopathological examination, and fungal tissue cultures are important to achieve organism identification along with molecular techniques such as species-specific PCR, ELISA, and counter immunoelectrophoresis.

Treatment / Management

Treatment of eumycetoma remains challenging. There are no definitive treatment protocol guidelines that have been established. Established treatment protocols are largely based on published case reports and case series.[7] Currently, treatment includes a combination of antifungal therapies and surgical procedures. Treatment starts with preoperative antifungal therapy for 6 months, followed by surgical procedures aimed at debulking and reducing the disease burden, followed by additional antifungal therapy for 6 months.[7] Some reported cases also showed improvement with medical therapy alone.[8][9][10]

Antifungals Used for the Treatment of Eumycetoma

Various classes of antifungals have been used in the treatment of eumycetoma, including azoles, amphotericin B, and terbinafine.

• Azoles: The azole antifungals are considered the "gold standard" for treatment.

  • Itraconazole is most frequently used. The dosage of itraconazole for the treatment of eumycetoma is 400 mg per day, divided into two doses for 12 months duration. Hepatoxicity is the principal chronic adverse effect.[11] Extended treatment duration has been an important predictor for achieving a higher cure rate. Eumycetoma patients may need to receive treatment from 6 months to 3 years.[12]
  • Newer azoles, such as voriconazole (400 mg to 600 mg per day) and posaconazole (800 mg per day), have also been trialed with good clinical outcomes.[10][13][14]
• Amphotericin B: Toxicity and need for hospitalization have greatly limited the use of amphotericin B. Liposomal amphotericin B has been used in select cases in endemic countries but lacks adequate response and the adverse effect of severe nephrotoxicity limits its use.[7] Intralesional amphotericin B has been used in select cases with a single lesion and has shown a good response but is not an effective treatment option in multilobulated lesions due to uneven drug diffusion and risk of dissemination.[15]
• Terbinafine: 500 mg twice a day for 24 to 48 weeks can also cause significant clinical improvement in 80% of cases.[16]

Surgical Therapy of Eumycetoma

 Authors of one study recommend a stepwise procedure, starting with initial preoperative treatment of eumycetomas with Itraconazole. It is thought that encapsulation of eumycetoma is promoted by therapy with antifungals. Thereby, the eumycetomas are better localized, and surgical debridement will be facilitated. Wide, extensive, disfiguring procedures can thus be avoided.[4]

Differential Diagnosis

• Lobomycosis - Chronic cutaneous fungal infection caused by Lacazia loboi, endemic to Central and South America. Lesions begin as papules and progress to keloid-like lesions that present as smooth nodules most commonly noted on hands, ears, and ankles. Mycetoma presents with sinus or fistula formation with the expulsion of granules. 
• Mycobacterium Marinum infection - Also is known as fish tank granuloma. Atypical mycobacterial infection that is contracted by contact with contaminated swimming pools, lakes, or ocean water. Clinically presents with tender red nodules on fingers or hands.
• Chromoblastomycosis - A subcutaneous fungal infection caused by dematiaceous fungi seen in tropical and subtropical climates. Typically presents in middle-aged men with crusted lesions affecting the lower extremities. 
• Histoplasmosis - Presents with umbilicated papules, nodules, or indurated ulcers. Associated lymphadenopathy is present. Risk factors for systemic involvement include immunosuppressed states. 
• Cutaneous tuberculosis- Clinically heterogeneous, presents as non-healing nodules, ulcers, plaque, or draining lymph nodes in patients from endemic areas.

Prognosis

Untreated, eumycetoma shows a slow but inevitable progression. When this condition is not recognized early or treatment is not available or not affordable; initially, painless eumycetomas can progress to limb destruction and amputation. Longer duration of therapy and lack of relapse in patient history are positive prognostic factors in studies that reviewed multiple cases of eumycetomas. Size of mycetomas from 5 to 10 cm or > 10 cm, using a combination of medical and surgical treatment were significant predictors of a good outcome.[4]

Deterrence and Patient Education

Given the pathogenesis of this disease, wearing shoes might prevent injuries that can lead to eumycetoma. Walking barefoot in highly endemic areas should be avoided whenever possible. Shoes protect feet while walking or working in areas that could lead to exposure to fungal elements present in water and soil. Early detection and treatment before the eumycetoma spread deeper across fascial planes can reduce disabilities from eumycetoma and improves outcomes.

Enhancing Healthcare Team Outcomes

Eumycetoma frequently poses a diagnostic and treatment dilemma. Eumycetoma occurs after a traumatic inoculation of filamentous fungi in barefoot walkers in endemic areas. Physical exam reveals nonhealing, chronic nodules and sinus tracts on the legs of many years duration. Access to health care in regions where eumycetoma is prevalent largely dictates the speed at which it is diagnosed and treatment is initiated.

While a dermatologist, infectious disease specialist, if accessible, are involved in the care of patients with eumycetoma, it is important to consult with an interprofessional team of specialists that include a general surgeon or foot surgeon for debulking of lesions. A pharmacist may also ensure oral antifungals are dosed appropriately in the early stages of treatment. Dermatopathologist is involved in the histopathological exam of biopsy specimens and determining an accurate diagnosis. Additional radiologic exams may be needed for long-standing, widespread infections. There are no definitive guidelines for the management of eumycetoma, but rather treatment regimens are based on case series and an exhaustive review of current medical literature from peer-reviewed journals.[4] [Level 1]

The outcomes of eumycetoma depend on a swift diagnosis and timely management. However, to improve outcomes, prompt consultation with an interprofessional group of specialists is recommended.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

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Disclosure: Sujitha Yadlapati declares no relevant financial relationships with ineligible companies.

Disclosure: Soham Chaudhari declares no relevant financial relationships with ineligible companies.