Eumycetoma

Eumycetoma is a chronic, progressive, granulomatous infection of the skin, subcutaneous tissue, fascia and bone caused by true fungi that form grains in tissue. It is the fungal form of mycetoma. The clinical triad is a painless subcutaneous swelling, multiple draining sinuses, and the discharge of grains.

The same clinical picture is caused by filamentous bacteria (actinomycetoma). The distinction determines therapy, because eumycetoma needs antifungal drugs and surgery, whereas actinomycetoma is treated with antibacterial drugs.

Eumycetoma is a neglected tropical disease. It occurs in the "mycetoma belt" between latitudes 15 degrees south and 30 degrees north, including Sudan (the highest burden), Somalia, Senegal, Mauritania, Chad, Niger, Nigeria, Kenya, Ethiopia, Yemen, India, Mexico and Venezuela. Cases appear in other regions through migration and travel.

Epidemiology:

• Young adult men aged 20 to 40, working as farmers, herders, labourers and field workers, who walk barefoot or carry wood and thorn branches on the back.
• Foot involvement in about 70 to 80 percent, and the hand, leg, back, thigh and buttock less commonly.
• Eumycetoma accounts for most cases in Sudan and in parts of the Sahel. Actinomycetoma dominates in Mexico and Central America.
• Late presentation, large lesions, and bone involvement are usual, because patients delay seeking care.

Black grains are formed by melanised fungi, pale grains by hyaline fungi. This is the first clue to the organism, and not a firm rule.

Reservoir: soil, thorny plants (acacia in Sudan), and decaying vegetation. Soil contaminated with animal dung and thorny acacia are the proposed sources of Madurella mycetomatis, but the ecological niche has not been established. The exact ecological niche is not established.

The fungus enters through minor trauma, typically a thorn prick or splinter on a barefoot lower limb. Implanted fungi grow in the subcutis and form a grain, a compact aggregate of hyphae in a cement matrix that protects the organism from immune attack and from drug penetration.

Pathogenic features:

• Grain formation is the central pathogenic process. In Madurella mycetomatis, the cement contains melanin and extracellular matrix.
• A neutrophil rich suppurative reaction surrounds the grain. A granulomatous reaction forms outside it, with macrophages, epithelioid cells, giant cells and fibrosis. The grain is progressively enclosed, and sinuses drain from abscesses to the skin.
• A Th2 skewed response and low interferon gamma production correlate with progression, and a Th1 response with limited disease. Antibodies are made and do not clear disease.
• Spread is by contiguous extension along fascial planes into muscle, tendon and bone, where destruction accumulates over years. Lymphatic spread to regional nodes occurs in about 10 percent, and haematogenous spread is rare.
• Susceptibility is male predominant. Women are affected less, and oestrogen has been proposed to inhibit growth, but the mechanism is not proven. Host genetic susceptibility, malnutrition and exposure are risk factors.

The incubation period is months to years, and the patient often does not recall the injury.

• A painless, firm subcutaneous nodule enlarges slowly, over months to years, into a swelling that deforms the part. Pain is minimal in the early stages, and bone pain or secondary infection produces tenderness.
• Multiple sinuses open in the skin, discharging serous or purulent fluid with grains of characteristic colour. Sinuses heal and re-form.
• The overlying skin is shiny, hyperpigmented, scarred and nodular, and there are satellite nodules.
• The foot is swollen and deformed ("Madura foot"), with loss of function.
• Bone involvement: periosteal reaction, cortical erosion and cavities occur, and ankle, tarsal and metatarsal bones are commonly destroyed.
• Secondary bacterial infection causes pain, fever, offensive discharge and cellulitis.
• Regional lymphadenopathy, nerve compression, joint contractures, and in advanced disease, ulceration, amputation and, rarely, death from sepsis or spread.
• Systemic features are unusual, and fever is absent unless there is bacterial infection.
• Staging (Mycetoma Research Centre classification): small localised lesions, medium lesions with muscle and fascia involvement, large lesions with bone destruction, and lesions with spread to other organs.

Red grains point to actinomycetoma caused by Actinomadura pelletieri, and black grains point to eumycetoma. Pale grains need microscopy or culture, because both groups produce them.

Diagnosis needs identification of the organism, because drug therapy depends on it.

• Grain examination: grains are collected from a discharging sinus by pressing the swelling and rinsing in sterile saline, or from a deep biopsy. Colour, size and consistency are recorded. Grains are crushed in 10 to 20 percent potassium hydroxide, which shows hyphae of 2 to 5 micrometres and swollen terminal cells in a brown cement matrix.
• Fine needle aspiration cytology: a minimally invasive method that can show grains, suppuration and granulomas, with a high positive rate where available.
• Deep surgical biopsy (open or core): the reference specimen. Superficial sinus swabs mostly grow bacteria. A deep wedge biopsy is divided for histology and culture.
• Histopathology: granulomas with a central suppurative zone, grains with surrounding Splendore Hoeppli material, neutrophils, plasma cells and giant cells, and fibrosis. Periodic acid Schiff and Grocott methenamine silver stain fungal hyphae, and Gram, Ziehl Neelsen and modified acid fast stains identify filamentous bacteria. Eosinophilic material around grains is common and is not diagnostic.
• Culture: Sabouraud dextrose agar with chloramphenicol, without cycloheximide, at 30 and 37 degrees Celsius for 4 to 6 weeks. Washed grains improve yield. Madurella mycetomatis grows slowly, and many cultures remain negative.
• Molecular identification: sequencing of the internal transcribed spacer region identifies the species, and species specific polymerase chain reaction is used for Madurella mycetomatis. Species identification also has a role in surveillance.
• Serology: counter immunoelectrophoresis, immunodiffusion and ELISA are used in a few centres, particularly for Madurella mycetomatis, with limited standardisation.
• Imaging:
  • Plain radiography: soft tissue swelling, periosteal reaction, cortical erosion, cavities in bone (3 to 5 mm lytic cavities in the metatarsals and tarsals), and sclerosis.
  • Ultrasonography: hyperechoic grains within hypoechoic granulomas, with echogenic walls, and tracts. A cheap, field applicable method.
  • Magnetic resonance imaging: the dot in circle sign, in which low signal dots (grains) lie in a high signal background on T2 weighted images, is highly suggestive of mycetoma, and MRI shows the extent of soft tissue and bone disease.
  • CT is used for bone involvement.
• Other tests: bacterial culture of discharge for secondary infection, full blood count, and HIV test.

Treatment is prolonged and often incomplete. The goals are cure, prevention of progression, and limb preservation. Early disease is far easier to treat than advanced disease.

Antifungal therapy

Treatment is guided by the organism:

• Madurella mycetomatis responds to itraconazole, ketoconazole and fosravuconazole.
• Scedosporium apiospermum responds to voriconazole, with itraconazole inferior.
• Fusarium species and Acremonium respond poorly to all drugs, and surgery plays a large role.
• Cure rates with drug therapy alone are modest. Combined medical and surgical treatment gives better results.

Surgical treatment

• Wide local excision: done after 6 or more months of antifungal treatment, when the lesion has become encapsulated and reduced in size. It is the strongest option for small, localised lesions.
• Debridement of bone and removal of necrotic bone when affected, with the drug course continuing.
• Amputation or disarticulation: for extensive bone destruction, advanced infection, intractable pain, severe sepsis, or failed medical therapy. Early amputation is common in endemic regions because patients present late, and recurrence at the stump occurs when disease extends beyond the surgical margin.
• Local control of sepsis: drainage of abscesses, and antibacterial therapy for secondary bacterial infection.
• Surgery without antifungal therapy has a high relapse rate.

Follow up and outcome

Review every 1 to 3 months with clinical measurement, ultrasonography or MRI, and liver function tests. Clinical cure is judged by closure of sinuses, absence of grains, resolution of swelling, and imaging evidence of resolution. Follow up continues for at least 1 to 2 years after treatment, because recurrence is common. Poor prognostic factors are large lesions, bone involvement, long disease duration, and Madurella mycetomatis infection in endemic settings.

Drug safety and monitoring

Itraconazole is hepatotoxic, negatively inotropic, and a strong CYP3A4 inhibitor. It is avoided in heart failure and pregnancy, with liver tests at baseline, 2 to 4 weeks and every 1 to 3 months. Ketoconazole causes dose related hepatotoxicity and adrenal suppression. Terbinafine is avoided in chronic or active liver disease and when creatinine clearance is below 50 mL per minute. Voriconazole and posaconazole need level monitoring and interaction review.

Actinomycetoma

Actinomycetoma is not a fungal infection and is not treated with antifungal drugs. Combined antibacterial therapy (for example co-trimoxazole with amikacin, or co-trimoxazole with amoxicillin clavulanate, depending on the species and severity) is the treatment, with a prolonged course. It is mentioned here to prevent the error of treating a bacterial mycetoma with an azole.

Wearing footwear and protective clothing in agricultural work, covering loads carried on the back, cleaning of puncture wounds, and early presentation of any painless swelling with sinuses. Education and primary care detection of early lesions in endemic communities improve outcomes. Lack of a known environmental source limits primary prevention.