Tuesday, December 6, 2016

From Unacknowledged to Simply “Neglected”: A Status Update on Mycetoma

by AN

In May of 2016, the 69th World Health Assembly met to discuss goals and priorities related to public health. During the assembly, a resolution was approved which recognized mycetoma as a neglected tropical disease (1). Mycetoma is a chronic infection caused by either fungi or bacteria. The most common cause of this disease is a fungi called Madurella mycetomatis. For patients affected by this disease and for their families, this recognition was a huge triumph. Only five months prior, NPR published a piece titled “A Disease So Neglected It’s Not Even On ‘Most-Neglected’ Lists”, which detailed the story of a young man in Sudan suffering from this disease (2). Neglected tropical diseases are defined as a group of communicable diseases which occur mainly in tropical climates. These diseases disproportionately affect populations that live in poverty. While mycetoma only graduated from being unacknowledged to the status of simply “neglected” this year, it is not a new disease. Cases have been reported since 1840 (3).  

Madurella mycetomatis was named for the place where it was first diagnosed, Madura, India in 1842 (4). This disease is often called “Madura foot” due to the part of the body which it frequently affects. Usually, the disease is caused by fungal cells entering a wound. While the foot is a common site of infection due to contact with the soil where M. mycetomatis lives, it can affect other parts of the body too. Initially, a small nodule forms at the site of infection. Over time, the nodule grows into a large mass. While the disease is often described as unsightly and putrid, the most profound effect of the disease is that it causes disability. The mass invades the bone, which causes disfigurement that can make it difficult to walk or even move. Though this disease is devastating, it is relatively rare, which is in part why it wasn’t even considered a neglected disease until this year. This disease is prevalent in many countries with a hot climate. The majority of cases that occur today are in Sudan, Mexico, and India (3). Sudan reports the highest number of cases every year, around 106. Males are significantly more affected by this disease than females. While a partial explanation for this may be that men spend more time outside, leading to more exposure, it doesn’t explain the level of disparity observed. One possible cause for the gender disparity may be due to inhibition of fungal growth by progesterone, a female hormone (4).  
A mass caused by M. mycetomatis (12)    
Due to the rarity of this disease, and the fact that it has only just begun to be acknowledged as a neglected disease, it has not been studied extensively. In fact, it has been studied very little. There is much to be learned about this debilitating disease. What little research that has been done has mainly focused on studying the formation of grains, which is an important feature of this fungi’s ability to cause disease. Grains are made up of dense fungal cells, surrounded by an extracellular matrix (4). An extracellular matrix is composed of non-living material secreted by cells, which provides structural support or protection. The matrix of grains is described as being cement-like, because it is so hard. The cement material is partially composed of host tissue (5). The structure of the grains is telling of their ability to cause disease. The two main features of grains attributed to disease and drug-resistance are the cement-like matrix and melanin, which is a pigment responsible for the black color of grains.

Black grains formed by M. mycetomatis (13)   
Melanin is found both in the fungal cell wall and the cement matrix surrounding cells. Melanin attracts heavy metals, which may contribute to the structure of the cement matrix, as metals provide rigidity. Melanin also protects the fungal cells from an individual’s immune system, and it is resistant to common anti-fungals used to treat M. mycetomatis (5). In addition to the administration of antifungals, treatment usually requires surgery. There are a limited number of antifungal drugs shown to be effective against M. mycetomatis. Ketoconazole is often used as the drug of choice, but its success rate is relatively poor (6). Other drugs shown to be somewhat successful at killing M. mycetomatis cells include voriconazole and fluconazole (7). While these drugs are only somewhat successful at killing M. mycetomatis cells, they are still better than the absence of treatment. However, “azole” drugs such as ketoconazole, itraconazole, voriconazole, and fluconazole, come with a high price tag (4). A jar of pills can cost over $40, which may not seem like a significant cost to Americans who collectively spend over $300 billion on prescriptions every year, but it is significant to families living in poverty in developing countries (8). The young Sudanese man in the NPR piece was unable to afford the necessary antifungals to treat his disease. He eventually got his leg amputated, but it was too late to save his life. Many individuals in countries where mycetoma is present cannot afford the drugs, let alone surgery. With the new designation of a Neglected Tropical Disease, there is hope that new drugs could be developed or old drugs could become more widely available.

            While research on this pathogen has been limited, there have been minor discoveries and triumphs over the past years that could lead to new therapies, especially as this disease reaches the high-priority status of “neglected”. Antifungals are the current treatment procedure, but identification of immunogens in recent years could become target candidates for a vaccine. An immunogen is a protein on a pathogen which causes an immune response in a host. This can be taken advantage of when developing a vaccine. Vaccines cause an immune response, which will “remember” the pathogen the next time it is encountered. Three different immunogens have been identified. All of these proteins are present in fungal grains, providing more evidence of the important role that grains play in causing disease (9, 10). Two of the immunogens are expressed in the cement-like part of the grain, while the other is expressed on the fungal cell. The identification of these proteins is important not just as potential targets of a vaccine, but as potential targets for diagnostics. Proper identification of the causative agent of this disease is important, as it determines the method of treatment. Mycetoma caused by fungi requires surgery, while mycetoma caused by bacteria usually does not, as bacteria respond better to available antibiotics than the fungi do to antifungals (4). Another triumph in studying this disease is the development of a mouse model for study (11). Disease in the mouse is also characterized by the formation of black grains. There is hope that with recognition of this disease as severely neglected, more resources will be allocated to studying it, and a model organism is vital for these studies. In most cases, being considered “neglected” would not be a positive thing. For the case of mycetoma, it’s a status upgrade.

1.     World Health Organization. 2016. Neglected tropical diseases. http://www.who.int/neglected_diseases/diseases/en/
2.     Maxmen, A. 2015. A disease so neglected it’s not even on ‘most-neglected’ lists. NPR: Goats and Soda, Stories of Life in a Changing World.
3.     Van de Sande, W.W.J. 2013. Global burden of human mycetoma: a systematic review and meta-analysis. PLOS Neglected Tropical Diseases.
4.     Ahmed, AOA, Leeuwen, W, Fahal, A, van de Sande, W, Verbrugh H, and A van Belkum. 2004. Mycetoma caused by Madurella mycetomatis: a neglected infectious burden. The Lancet Infectious Diseases. 4(9): 566-574.
5.     Van de Sande, W.W.J, Kat, J.D., Coppens, J., Ahmed, A.O.A., Fahal, A., Verbrugh, H., and A. van Belkum. 2007. Melanin biosynthesis in Madurella mycetomatis and its effect on susceptibility to itraconazole and ketoconazole. Microbes and Infection. 9(9): 1114-1123.
6.     Ahmed, A.O.A, van de Sande W.W.J, van Vianen, W., van Belkum, A., Fahal, A.H., Verbrugh, H.A., and I.A.J.M. Bakker-Woudenberg. 2004. In Vitro Susceptibilities of Madurella mycetomatis to Itraconazole and Amphotericin B Assessed by a Modified NCCLS Method and a Viability-Based 2,3-Bis(2-Methoxy-4-Nitro-5- Sulfophenyl)-5-[(Phenylamino)Carbonyl]-2H- Tetrazolium Hydroxide (XTT) Assay. Antimicrob. Agents Chemother. 48(7):2742-2746.
7.     Van de Sande, W.W.J., Luijendijk, A., Ahmed, A.O.A., Bakker-Woudenberg, I.A.J.M., and A. van Belkum. 2005. Antimicrob. Agents Chemother. 49(4):1364-1368.
8.     Chicago Tribune. 2016. Report: Americans spent 8.5 percent more on prescription drugs in 2015.
9.     De Klerk, N., de Vogel, C., Fahal, A., van Belkum, A., and W.W.J. van de Sende. 2011. Med Mycol. 50(2):143-151.
10.  Van de Sande, W.W.J., Janse, D.J., Hira, V., Goedhart, H., van der Zee, R., Ahmed, A.O.A., Ott, A., Verbrugh, H., and A. van Belkum. 2006. Journal of Immunology. 177(3):1997-2005.
11. Ahmed, A.O.A., van Vianen, W., ten Kate, M.T., van de Sande, W.W.J., van Belkum, A., Fahal, A.H., Verbrugh, H.A., Bakker-Woudenberg, I.A.J.M. 2003. A murine model of Madurella mycetomatis eumycetoma. Immunology & Medical Microbiology. 37(1):29-36.
12.  Van de Sande, W.W.J, Janse DJ, Hira V., Goedhart H., van der Zee R., Ahmed AOA., Ott A., Verbrugh H., and A. van Belkum. 2006. Translationally controlled tumor protein from Madurella mycetomatis, a marker for tumorous mycetoma progression. J. Immunol. 177:1997-2005.
13. Estrada-Chavez G., Vega-Memije M., Arenas R., Chavez-Lopez G., Estrada-Castanon R., Fernandez R., Hay R., and J. Dominguez-Cherit. 2009. Eumycotic mycetoma caused by Madurella mycetomatis successfully treated with antifungals, surgery, and topical negative pressure therapy. International Journal of Dermatology. 48(4):401-403.

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