Mycetoma(Bacterial and Fungal Disease)

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Mycetoma
Brijesh Singh Yadav [email protected]

Disease Type: Both Fungal & Bacterial Disease Causative Agent: Actinomycotic Mycetoma, eumycetoma Common Name: Madura Foot, Fungus ball, Aspergilloma Disease description: Mycetoma is a chronic, granulomatous disease of the skin and subcutaneous tissue, which sometimes involves muscle, bones, and neighboring organs. It is characterized by tumefaction, abscess formation, and fistulae. It typically affects the lower extremities, but it can occur in almost any region of the body. Mycetoma predominately occurs in farm workers, but it can also occur in the general population. The infection can be caused by true fungi (eumycetoma) in 40%, or filamentous bacteria (actinomycetoma) in 60%. Also known as Pulmonary aspergilloma.(1) , Mycetoma is a chronic subcutaneous infection which results in a granulomatous inflammatory response in the deep dermis and subcutaneous tissue, and can extend to the underlying bone. Mycetoma is characterized by the formation of grains containing aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses. This disease was described first in the mid 1800s and initially named Madura foot, after the region of Madura in India where it first was identified. (2) Pseudoallescheria boydii is one of many eumycetoma fungi spp. that causes the fungal form of madura foot . The disease is characterized by a yogurt-like discharge upon maturation of the infection.

Fig.1. Mycetoma showing numerous draining sinuses. There is destruction of bone, distortion of the foot, and hyperplasia at the openings of the sinustracts. 2. Excised mycetoma showing a draining sinus (cut open in this preparation) containing black grains.

Causes of Disease:

Owing to a wound, bacteria or fungi gain entry into the skin. Approximately one month or more after the injury, a nodule forms under the skin surface. The nodule is painless, even as it increases in size over the following months. Eventually, the nodule forms a tumor, or mass of abnormal tissue. The tumor contains cavities-called sinuses-that discharge blood- or pus-tainted fluid. The fluid also contains tiny grains, less than two thousandths of an inch in size. The color of these grains depends on the type of bacteria or fungi causing the infection. As the infection continues, surrounding tissue becomes involved, with an accumulation of scarring and loss of function. The infection can extend to the bone, causing inflammation, pain, and severe damage. Mycetoma may be complicated by secondary infections, in which new bacteria become established in the area and cause an additional set of problems (11).

Risk Factors:
Mycetoma typically presents in agricultural workers (hands, shoulders and back - from carrying contaminated vegetation and other burdens), or in individuals who walk barefoot in dry, dusty conditions. Minor trauma allows pathogens from the soil to enter the skin (6)

Causative Agent Description:
Pathogen Name: Actinomycotic Mycetoma, Pathogen Description:  Actinomycetoma is a mycetomal disease affecting the skin and connective tissue. It is characterized by formation of granules containing branched filaments. The characteristic granules formed during the course of infection drain via formation of sinuses.  It is researched by the Mycetoma Research Center, which is part of The University of Khartoum, located in Khartoum, Sudan.  Actinomadura is a genus of aerobic, Gram-positive, non-acid-fast fungi where filaments fragment into spores. Actinomadura pelletieri is an agent of mycetoma.  Eumycetoma Pseudallescheria is a filamentous fungus that is found worldwide. It has so far been isolated from soil (7), sewage, contaminated water, and the manure of farm animals. It is an emerging opportunistic pathogen and can cause various infections in humans. The infections caused by Pseudallescheria boydii are occasionally and wholely referred to as pseudallescheriasis. Pseudallescheria boydii is among the causative agents of white grain mycetoma.

Fig.1.Actinomycotic mycetoma

2. Eumycotic mycetoma due to the fungus Pseudallescheria boydii 3.Actinomycotic Mycetoma, Foot

Taxonomic classification:
Actinomadura is an aerobic actinomycetes, Actinomadura is a filamentous bacterium found in soil. Although it was once believed to be a fungus, the information later attained about its ultrastructural cellular properties showed that Actinomadura is in fact an aerobic actinomycetes. However, for the reason that most of the diagnostic procedures related to Actinomadura are still held in mycology laboratories in many centers.

Morphology & toxin Production:
The growth rate of Actinomadura is slow. It grows on routine mycologic or mycobacteriologic media and under aerobic conditions. The colony has a glabrous, waxy, membranous or mucoid, heaped and folded appearance. The color of the colony is red, pink, yellow, orange, white, or tan. Following two weeks of incubation, aerial hyphae may develop on the surface, particularly on Lowenstein-Jensen medium. Actinomadura is Gram positive and nonacid-fast. The typical structures are the filaments, which are nonfragmenting and narrow (0.5-1 µm in diameter). These filaments branch abundantly. Chains of round conidia may occasionally be produced from the aerial hyphae, particularly on slide cultures. (12)

Fig. At higher magnification, the colony of organisms floats in sea of pus. Organizing granulation tissue outlines the defect.

Fig. The tissue above the lower 1/4 of the field is granulation tissue. The two darker zones in the granulation tissue are areas of suppuration. In the zone of suppuration to the left, green arrows identify a colony of organisms. The colony is a “grain” (mycetoma)

Taxonomic Classification:
Kingdom Phylum Class Order Family Genus Fungi Ascomycota Euascomycetes Microascales Microascaceae Pseudallescheria Conidiophores with conidia of Pseudallescheria boydii

Morphology:
Pseudallescheria is a homothallic fungus. Colonies of Pseudallescheria boydii grow rapidly at 25°C. The texture is wooly to cottony. From the front, the color is initially white and later becomes dark gray or smoky brown. From the reverse, it is pale with brownish black zones. (9) Pseudallescheria is a filamentous fungus that is found worldwide
(8)

Taxonomic Classification:
Kingdom Phylum Class Order Family Genus Fungi Ascomycota Euascomycetes Microascales Microascaceae Pseudallescheria

Fig. Pseudallescheria boydii (anamorph Scedosporium apiospermum) on Sabouraud's dextrose agar showing typical greyish-white, cottony colony with a greenish-black reverse.

Morphology and toxin production:
Pseudallescheria is a homothallic fungus. Colonies of Pseudallescheria boydii grow rapidly at 25°C. The texture is wooly to cottony. From the front, the color is initially white and later becomes dark gray or smoky brown. From the reverse, it is pale with brownish black zones. (9). The morphological features of the fungomas vary between involved organs, with those in the lung showing well-defined layers of peripheral mycelial hypocellularity and hypercellularity consisting of anneloconidiophores and conidia. The fungomas in all organs are derived from necrotic host tissue, which resulted from nodular infarction due to fungal invasion and thrombosis of blood vessels. (10) MORPHOLOGY OF THE GRAINS (GRANULES) IN MYCETOMAS: Eumycetomas: Madurella mycetomatis: Large granules (up to 5 mm or more) with interlacing hyphae embedded in interstitial brownish matrix; hyphae st periphery arranged radially with numerous chlamydospores. Petriellidium boydii: Eosinophilic, lighter in the center; numerous vesicles or swollen hyphae; peripheral eosinophilic fringe; other pale eumycetomas have a minimal fringe and contain a dense mass of intermeshing hyphae. Actinomycetomas: Actinomadura madurae: Large (1 - 5 mm and large) and multilobulate; peripheral basophilia and central eosinophilia or pale staining; filaments grow from the peripheral zone. Streptomyces somaliensis: Large (0.5 - 2 mm or more) with dense thin filaments; often stains homogeneously; transverse fracture lines. Nocardia brasiliensis: Small grains (approximately 1 mm); central purple zone ; loose clumps of filaments ; Gram-positive delicate branching filaments breaking up into bacillary and coccal forms ; Gram-negative amorphous matrix.

History:
For Eumycetoma, Gill, who worked at a dispensary in the southern Indian province of Madura, first recognized mycetomas as a disease entity in 1842. Godfrey first documented a case of mycetoma in Madras, India. Native peoples of the province of Madura commonly called the disease Madura foot. In 1860, Carter, who established the fungal etiology of this disorder, first proposed the term mycetoma. In 1872, Carter further proposed the terms melanoid and ochroid in an attempt to classify the disease into 2 varieties on the basis of the black or pale-colored granules (i.e., grains, sclerotia) produced by the etiologic agents. (2)

Epidemiology:
The disease is endemic in the tropics and subtropics and is named after the region of India where it was first described in 1842. • Although currently uncommon in temperate regions, it does occur in the southern USA, and cases are found in the homeless, and AIDS sufferers. • The incidence of mycetoma is likely to rise in temperate regions due to increases in worldwide travel, and since mycoses are not notifiable, the incidence in the UK is unknown.

Disease Transmission:
The causative organism enters through sites of local trauma (eg, cut on the hand, foot splinter, local trauma related to carrying soil-contaminated material). A neutrophilic response initially occurs, which may be followed by a granulomatous reaction. Spread occurs through skin facial planes and can involve the bone. Hematogenous or lymphatic spread is uncommon. (2) Mechanism: Bacteria causing Actinomycetoma has a thick wall surrounding the cytoplasmic membrane which is rich in lipid & carbohydrate compound. Some of these compounds such as lipoarabinomamman & mycoloc acids have been identified as virulence factors.These bacteria are capable of blocking the adequate killing mechanism of the cells of the infected hosts. However, it is considered that they have low pathogenic potential & most of them live as saprophytes in the soil.(13) Signs and symptoms of disease: Many patients have no symptoms. When symptoms do develop, they can include:
• • • • •

Cough Coughing up blood (seen in up to 75% of patients) Chest pain Shortness of breath Wheezing

• •

Unintentional weight loss Fever(1)

Diagnosis:
Diagnosis of mycetoma is usually accomplished by radiology,ultrasound or by fine needle aspiration of the fluid within an afflicted area of the body. Exams and Tests
• • • • •

Chest x-ray Chest CT Sputum culture Bronchoscopy or bronchoscopy with lavage (BAL) Serum precipitins for aspergillus (blood test to detect antibodies to aspergillus)(1)

Fig. H&E stained tissue section showing blacked grained eumycotic mycetoma caused by Madurella mycetomatis.

Treatment:
Combating mycetoma requires both surgery and drug therapy. Surgery usually consists of removing the tumor and a portion of the surrounding tissue. If the infection is extensive, amputation is sometimes necessary. Drug therapy is recommended in conjunction with surgery. The specific prescription depends on the type of bacteria or fungi causing the disease. (11)Actinomadura madurae is usually susceptible to a combination of streptomycin and dapsone Single or combination treatment is used:
• • • • •

Streptomycin injections Oral cotrimoxasol (Apo-Sulfatrim®, Bactrim®, Septrin®, Trimel®, Trisul®) Amikacin (Amikin®) Dapsone Rifampicin (Rifidin®)

• •

Minocycline (Minomycin®, Minotabs®). Sulfamethoxazole

Eumycetoma is more difficult to treat.
• • •

Itraconazole Ketoconazole Surgery to remove the affected tissue completely. These may mean amputation if bone is involved. (3)

One proposed treatment protocol involves gentamicin, cotrimoxazole, and doxycycline(5)

Geographical Distribution:
Mycetoma, or Madura Foot, is a disease prevalent in arid and semi-arid regions around the globe. It is found in Brazil,Mexico,the Sahel,in pan-Arabia,and in semi-arid areas of India.It is found as far north as Romania and United States. Eumycetoma is mainly a disease of the tropical and subtropical zones especially between the Tropic of Cancer and the Tropic of Capricorn, that is, between the latitudes 15° S and 30° N. Eumycetoma is endemic in India, parts of Africa (eg, Sudan, Senegal, Somalia, Nigeria, Zaire, Chad), Pakistan, Yemen, Mexico, Central America, South America (eg, Guatemala, Venezuela, Colombia, Brazil), and Indonesia (2). In general, the geographic distribution of the various mycetoma agents is related to the amount of rainfall and other climatic conditions. Each geographic region has a different list of most common agents. (2).

Disease Statistics:
• • • • It is not endemic in New Zealand but mycetoma is occasionally diagnosed in native Pacific Islanders. Mycetoma is more common in men than women; particularly those aged 20 to 50.
(3)

The male-to-female ratio is 183:81(2). For eumycetoma, the disease incidence is higher in males than females, with a ratio of 4-5:1 & in persons aged 10-40 years. . (2)

Sources:
1. 2. 3. 4. 5. 6. Medline plus eMedicine Dermnet NZ University of Maryland Medical Centre Indian journal of dermatology, venereology and leprology Patient UK

7. Summerbell, R. C., S. Krajden, and J. Kane. 1989. Potted plants in hospitals as reservoirs of pathogenic fungi. Mycopathologia. 106:13-22. 8. Fernandez-Guerrero, M. L., P. Ruiz-Barnes, and J. M. Ales. 1987. Postcraniotomy mycetoma of the scalp and osteomyelitis due to Pseudallescheria boydii `letter. J Infect Dis. 156:855. 9. de Hoog, G. S., J. Guarro, J. Gene, and M. J. Figueras. 2000. Atlas of Clinical Fungi, 2nd ed, vol. 1. Centraalbureau voor Schimmelcultures, Utrecht, The Netherlands 10. Mycology Online-University of Adelaide, Australia 11. Health A to Z 12. Larone, D. H. 1995. Medically Important Fungi - A Guide to Identification, 3rd ed. ASM Press, Washington, D.C. 13. Principles and Practice of Travel Medicine by Jane N. Zuckerman

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