Hand Mycetoma: The Mycetoma Research Centre Experience and Literature Review

Mycetoma is a devastating, neglected tropical disease characterised by extensive tissue involvement resulting in destruction, deformities and disabilities in the affected patients. The hand is commonly affected by mycetoma thus compromises its functionality and hinder the patient’s daily activities of living. In this communication, we report on 533 patients with hand mycetoma managed over a period of 24 years at the Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan. Eumycetoma was the commonest type of mycetoma (83.3%) encountered. Males were predominately affected (69.2%) with a sex ratio of 2.2:1. The majority of the patients (84%) were young adult below the age of 40 years old at presentation. The generality of patients (86.4%) were from the Sudan mycetoma belt. Children and adolescents (28.1%), farmers (18.2%) and workers (17.4%) were more frequently affected. The majority of patients (67.4%) had disease duration of less than 5 years at presentation. The study, did not document significant history of local trauma, familial tendency, concomitant medical diseases or other predisposing cause for mycetoma in this population. Pain (23.1%) was not a disease feature in this series and 52% of patients had past surgery for mycetoma and recurrence. The right hand was affected most (60.4%), and 64% of them had small lesion at presentation. Conventional x-ray was only helpful in patients with advanced disease and the MRI accurately determined the disease extension. Cytological smears, surgical biopsies histopathological examination and grains culture were the principal diagnostic tools for causative organisms’ identification. In the present series it was difficult to determine the treatment outcome due to high patients follow up dropout.     

The Epidemiology of Mycetoma

Mycetoma is one of the badly neglected health problems across the globe. It is commonly seen in tropical and subtropical regions. It is a chronic subcutaneous granulomatous destructive inflammatory disease which eventually invades deep structures and bones and produce massive deformity and disability. Mycetoma has high morbidity, and can be fatal. However, its incidence, prevalence and route of infection as well as its susceptibility and resistance are not properly understood. This knowledge gap has badly affected patient management and proper planning for mycetoma preventive measurements.     

Mycetoma in the Sudan: An Update from the Mycetoma Research Centre,University of Khartoum,Sudan

This communication reports on the Mycetoma Research Centre of the University of Khartoum, Sudan experience on 6,792 patients seen during the period 1991–2014.The patients were predominately young (64% under 30 years old) males (76%). The majority (68%) were from the Sudan mycetoma belt and 28% were students. Madurella mycetomatis eumycetoma was the most common type (70%). In 66% of the patients the duration of the disease was less than five years, and 81% gave a history of sinuses discharging mostly black grains (78%). History of trauma at the mycetoma site was reported in 20%. Local pain was reported in 27% of the patients, and only 12% had a family history of mycetoma. The study showed that 57% of the patients had previous surgical excisions and recurrence, and only 4% received previous medical treatment for mycetoma. Other concomitant medical diseases were reported in 4% of the patients. The foot (76%) and hand (8%) were the most commonly affected sites. Less frequently affected sites were the leg and knee (7%), thigh (2%), buttock (2%) and arm and forearm (1%). Rare sites included the chest wall, head and neck, back, abdominal wall, perineum, oral cavity, tongue and eye. Multiple sites mycetoma was recorded in 135 (2%) of cases. At presentation, 37% of patients had massive lesions, 79% had sinuses, 8% had local hyper-hydrosis at the mycetoma lesion, 11% had regional lymphadenopathy, while 6% had dilated tortuous veins proximal to the mycetoma lesions. The diagnosis of mycetoma was established by combined imaging techniques and cytological, histopathological, serological tests and grain culture. Patients with actinomycetoma received a combination of antimicrobial agents, while eumycetoma patients received antifungal agents combined with various surgical excisions. Surgical excisions in the form of wide local excision, debridement or amputation were done in 807 patients, and of them 248 patients (30.7%) had postoperative recurrence. Different types of amputations were done in 120 patients (1.7%).     

Mycetoma: Experience of 482 Cases in a Single Center in Mexico

Mycetoma is a chronic granulomatous disease. It is classified into eumycetoma caused by fungi and actinomycetoma due to filamentous actinomycetes. Mycetoma can be found in geographic areas in close proximity to the Tropic of Cancer. Mexico is one of the countries in which this disease is highly endemic. In this retrospective study we report epidemiologic, clinical and microbiologic data of mycetoma observed in the General Hospital of Mexico in a 33 year-period (1980 to 2013). A total of 482 cases were included which were clinical and microbiology confirmed. Four hundred and forty four cases (92.11%) were actinomycetomas and 38 cases (7.88%) were eumycetomas. Most patients were agricultural workers; there was a male predominance with a sex ratio of 3∶1. The mean age was 34.5 years old (most ranged from 21 to 40 years). The main affected localization was lower and upper limbs (70.74% and 14.52% respectively). Most of the patients came from humid tropical areas (Morelos, Guerrero and Hidalgo were the regions commonly reported). The main clinical presentation was as tumor-like soft tissue swelling with draining sinuses (97.1%). Grains were observed in all the cases. The principal causative agents for actinomycetoma were: Nocardia brasiliensis (78.21%) and Actinomadura madurae (8.7%); meanwhile, for eumycetomas: Madurella mycetomatis and Scedosporium boydii (synonym: Pseudallescheria boydii) were identified. This is a single-center, with long-follow up, cross-sectional study that allows determining the prevalence and characteristics of mycetoma in different regions of Mexico.     

Predictors of Post-operative Mycetoma Recurrence Using Machine-Learning Algorithms: The Mycetoma Research Center Experience

Post-operative recurrence in mycetoma after adequate medical and surgical treatment is common and a serious problem. It has health, socio-economic and psychological detrimental effects on patients and families. It is with this in mind, we set out to determine the predictors of post-operative recurrence in mycetoma. The study included 1013 patients with Madurella mycetomatis causing eumycetoma who underwent surgical excision at the Mycetoma Research Centre, Khartoum, Sudan in the period 1991–2015. The clinical records of these patients were reviewed and relevant information was collected using a pre-designed data collection sheet. The study showed, 276 patients (27.2%) of the studied population developed post-operative recurrence, 217 were males (78.6%) and 59 were females (21.4%). Their age ranged between 5 to 70 years with a mean of 32 years. The disease duration at presentation ranged between 2 months and 17 years. The majority of the patients 118 (42.8%) had mycetoma of 1 year duration. In this study, students were the most affected; 105 (38%) followed by workers 70 (25.4%), then farmers 48(17.3%). The majority of the patients were from the Central Sudan 207 (75%), Western Sudan 53 (19.2%) while 11 patients (4%) were from the Northern part. Past history of surgical intervention performed elsewhere was reported in 196 patients (71.1%). Family history of mycetoma was reported in 50 patients (18.1%). The foot was the most affected site, 245 (88.7%), followed by the hand seen in 19 (6.8%) patients and 44 (4.5%) had different sites involvement. Most of the patients 258 (93.5%) had wide local surgical excisions while 18 had major amputation. The model predicted that the certain groups have a high risk of recurrence, and these include patients with disease duration greater than 10 years and extra-pedal mycetoma. Patients with disease duration between [5–10] years, with pedal mycetoma, who had previous surgery, with positive family history and underwent wide local surgical excision. Patients with disease duration [5–10] years, with pedal mycetoma, had previous surgery, with no family history but presented with a disease size (> 10 cm), were non- farmers and underwent wide local surgical excision. Other groups are patients with disease duration (≤5 years), with pedal mycetoma, age <59 years, living in the Western /Eastern / Southern regions of the Sudan and with positive family history and had wide local surgical excision. Also included patients with disease duration (≤5 years), with pedal mycetoma, aged <59 years, living in the northern or central region, with no family history but presented with a disease size >10 cm, working as farmers or students and underwent wide local surgical excision. In conclusion, these groups of patients need special care to reduce the incidence of post-operative recurrence with its morbidity and detrimental consequences. In depth studies for the other predisposing factors for post-operative recurrence such as genetic, immunological and environmental factors are needed.     

Mycetoma: a clinical dilemma in resource limited settings

Background

Mycetoma is a chronic mutilating disease of the skin and the underlying tissues caused by fungi or bacteria. Although recently included in the list of neglected tropical diseases by the World Health Organization, strategic control and preventive measures are yet to be outlined. Thus, it continues to pose huge public health threat in many tropical and sub-tropical countries. If not detected and managed early, it results into gruesome deformity of the limbs. Its low report and lack of familiarity may predispose patients to misdiagnosis and delayed treatment initiation. More so in situation where diagnostic tools are limited or unavailable, little or no option is left but to clinically diagnose these patients. Therefore, an overview of clinical course of mycetoma, a suggested diagnostic algorithm and proposed use of materials that cover the exposed susceptible parts of the body during labour may assist in the prevention and improvement of its management. Furthermore, early reporting which should be encouraged through formal and informal education and sensitization is strongly suggested.

Main text

An overview of the clinical presentation of mycetoma in the early and late phases, clues to distinguish eumycetoma from actinomycetoma in the field and the laboratory, differential diagnosis and a suggested diagnostic algorithm that may be useful in making diagnosis amidst the differential diagnosis of mycetoma is given. Additionally, a proposed preventive measures which may be helpful in the community is also provided. Since treatment is currently based on expert opinion, we encourage active research to establish treatment guideline for it.

Conclusion

Since delay in visiting health facility results into gruesome complication, early presentation, recognition and initiation of appropriate choice of regimen is helpful in reducing complications. The clinical overview of mycetoma and the suggested algorithm may enhance suspicion and possibly increase recognition of mycetoma in the community and further guide in differentiation of eumycetoma from actinomycetoma. There is an urgent need for research funding for mycetoma, a disease plagued by severe physical disabilities and social stigma leading to isolation.

     

The Mycetoma Knowledge Gap: Identification of Research Priorities

Mycetoma is a tropical disease which is caused by a taxonomically diverse range of actinomycetes (actinomycetoma) and fungi (eumycetoma). The disease was only recently listed by the World Health Organization (WHO) as a neglected tropical disease (NTD). This recognition is the direct result of a meeting held in Geneva on February 1, 2013, in which experts on the disease from around the world met to identify the key research priorities needed to combat mycetoma. The areas that need to be addressed are highlighted here. The initial priority is to establish the incidence and prevalence of the disease in regions where mycetoma is endemic, prior to determining the primary reservoirs of the predominant causal agents and their mode of transmission to susceptible individuals in order to establish novel interventions that will reduce the impact of the disease on individuals, families, and communities. Critically, economical, reliable, and effective methods are required to achieve early diagnosis of infections and consequential improved therapeutic outcomes. Molecular techniques and serological assays were considered the most promising in the development of novel diagnostic tools to be used in endemic settings. Improved strategies for treating eumycetoma and actinomycetoma are also considered.     

Global Burden of Human Mycetoma: A Systematic Review and Meta-analysis

Mycetoma is a chronic infectious disease of the subcutaneous tissue with a high morbidity. This disease has been reported from countries between 30°N and 15°S since 1840 but the exact burden of disease is not known. It is currently unknown what the incidence, prevalence and the number of reported cases per year per country is. In order to estimate what the global burden of mycetoma is, a meta-analysis was performed. In total 50 studies were included, which resulted in a total of 8763 mycetoma cases. Most cases were found in men between 11 and 40 years of age. The foot was most commonly affected. Most cases were reported from Mexico, Sudan and India. Madurella mycetomatis was the most prevalent causative agent world-wide, followed by Actinomadura madurae, Streptomyces somaliensis, Actinomadura pelletieri, Nocardia brasiliensis and Nocardia asteroides. Although this study represents a first indication of the global burden on mycetoma, the actual burden is probably much higher. In this study only cases reported to literature could be used and most of these cases were found by searching archives from a single hospital in a single city of that country. By erecting (inter)national surveillance programs a more accurate estimation of the global burden on mycetoma can be obtained.     

A Call to Action for Mycetoma

Purpose of Review

Here, we discuss the current needs and priorities for mycetoma control and prevention, highlight lessons learned from leprosy and podoconiosis, and motivate an urgent need to accelerate progress toward reducing the burden of mycetoma in endemic areas.

Recent Findings

In 2015, the World Health Assembly (WHA) added mycetoma, a progressively debilitating disease caused by fungi and bacteria, to the World Health Organization (WHO) list of priority neglected tropical diseases (NTDs). Designation of other diseases as NTDs has raised awareness, enabled global partnerships, and advanced the capacity to combat disease through integrated programming. Although key mycetoma etiologic agents have been identified, many questions remain and mycetoma may similarly benefit from NTD designation.

Summary

In collaboration with experts at WHO and elsewhere, we formed a global mycetoma working group to connect partners from a variety of sectors and specialties. We envision that this group will evolve into a formalized partnership that can prioritize strategic planning, advocacy, and research needs, identify funding sources, and coordinate activities related to mycetoma and other NTDs affecting the skin. The experiences gained from other NTDs can help to guide the global mycetoma working group’s activities to better address the goals set forth in the WHA resolution.

     

Mycetoma Herbal Treatment: The Mycetoma Research Centre,Sudan Experience

It is still challenging and difficult to treat patients with eumycetoma; the current treatment has many side effects and has proven to be expensive and characterized by high recurrence rate, hence the poor patients'' treatment compliance. Most of the patients are of low socio-economic status, have many financial constraints and hence, many of them rely on alternative and herbal medicine for the treatment of their disease. With this background, the current study was conducted to determine the prevalence of herbal medicine usage among patients with eumycetoma. This cross-sectional, observational, questionnaire-based study was conducted at the Mycetoma Research Center, University of Khartoum, Khartoum, Sudan. A convenience cohort of 311 patients with confirmed eumycetoma was invited to participate in the study after informed consent. The study showed that 42.4% of the study population used herbal medicine for the treatment of eumycetoma at some stage of their illness. The commonly used herbs were Moringa oleifera, Acacia nilotica, Citrullus colocynthis and Cuminum cyminum. Most of the patients claimed no benefits from the herbal treatment. Ninety one patients (29.3%) had encountered complications with herbal treatment. The high prevalence of herbal treatment encountered in the study can be explained by the patients'' dissatisfaction with the current medical therapeutic modalities. To reduce the high prevalence of herbal medicine usage, governmental control and health policies are mandatory; likewise, native healers need to be educated in that. Moringa oleifera was the commonly used herb in this study and many reports claimed medicinal properties of this tree; hence, further in-depth studies to determine the active ingredients in the different parts of the tree and its effect are required.     

Pulmonary Madurella mycetomatis mycetoma secondary to knee eumycetoma,Senegal

Mycetoma is a neglected tropical disease which is endemic in Senegal. Although this subcutaneous mycosis is most commonly found on the foot, extrapodal localisations have also been found, including on the leg, knee, thigh, hand, and arm. To our knowledge, no case of blood-spread eumycetoma has been reported in Senegal. Here, we report a case of pulmonary mycetoma secondary to a Madurella mycetomatis knee eumycetoma. The patient was a 41-year-old farmer living in Louga, Senegal, where the Sudano-Sahelian climate is characterised by a short and unstable rainy season and a steppe vegetation. He suffered a trauma to the right more than 20 years previously and had received treatment for more than 10 years with traditional medicine. He consulted at Le Dantec University Hospital in Dakar for treatment of a right knee mycetoma which had been diagnosed more than 10 years ago. He had experienced a chronic cough for more than a year; tuberculosis documentation was negative. Grains collected from the knee and the sputum isolated M. mycetomatis, confirmed by the rRNA gene ITS regions nucleotide sequence analysis. An amputation above the knee was performed, and antibacterial and antifungal therapy was started with amoxicillin-clavulanic acid and terbinafine. The patient died within a month of his discharge from hospital.     

Mapping the Potential Risk of Mycetoma Infection in Sudan and South Sudan Using Ecological Niche Modeling

In 2013, the World Health Organization (WHO) recognized mycetoma as one of the neglected tropical conditions due to the efforts of the mycetoma consortium. This same consortium formulated knowledge gaps that require further research. One of these gaps was that very few data are available on the epidemiology and transmission cycle of the causative agents. Previous work suggested a soil-borne or Acacia thorn-prick-mediated origin of mycetoma infections, but no studies have investigated effects of soil type and Acacia geographic distribution on mycetoma case distributions. Here, we map risk of mycetoma infection across Sudan and South Sudan using ecological niche modeling (ENM). For this study, records of mycetoma cases were obtained from the scientific literature and GIDEON; Acacia records were obtained from the Global Biodiversity Information Facility. We developed ENMs based on digital GIS data layers summarizing soil characteristics, land-surface temperature, and greenness indices to provide a rich picture of environmental variation across Sudan and South Sudan. ENMs were calibrated in known endemic districts and transferred countrywide; model results suggested that risk is greatest in an east-west belt across central Sudan. Visualizing ENMs in environmental dimensions, mycetoma occurs under diverse environmental conditions. We compared niches of mycetoma and Acacia trees, and could not reject the null hypothesis of niche similarity. This study revealed contributions of different environmental factors to mycetoma infection risk, identified suitable environments and regions for transmission, signaled a potential mycetoma-Acacia association, and provided steps towards a robust risk map for the disease.     

Mycetoma in the Togolese: An Update from a Single-Center Experience

Background

Mycetoma is a chronic inflammatory process caused either by fungi (eumycetoma) or bacteria (actinomycetoma). In this retrospective study, we report epidemiologic and histopathological data of mycetoma observed in the Lome Hospital, Togo in a 25-year period (1992–2016).

Methodology

This is a retrospective study, over a period of 25 years, to analyze epidemiological and etiological findings of mycetomas seen in the single laboratory of pathological anatomy of the Lomé, Togo.

Results

A total of 61 cases were retrieved from which only 33 cases were included which where clinically and microbiologically confirmed. The mean age of the patients was 29.7?±?1.34 and a sex ratio (M/F) of 1.5. The majority of patients were farmers (n?=?23 cases; 69.7%). Diagnosed etiologic agents were fungal in 24 cases (72.7%) and actinomycotic cases in 9 cases (27.3%). The fungal mycetomas consisted of Madurella mycetomatis (black grains) and Falcifomispora senegaliensis (black grains). The actinomycotic agents were represented by Actinomadura madurae (white grains), Actinomadurae pelletieri (red grains) and Nocardia sp. (yellow grains).

Conclusion

This report represents a single-center study which provides epidemiologic and histopathological data of mycetoma cases in Togo.

     

Merits and Pitfalls of Currently Used Diagnostic Tools in Mycetoma

Treatment of mycetoma depends on the causative organism and since many organisms, both actinomycetes (actinomycetoma) and fungi (eumycetoma), are capable of producing mycetoma, an accurate diagnosis is crucial. Currently, multiple diagnostic tools are used to determine the extent of infections and to identify the causative agents of mycetoma. These include various imaging, cytological, histopathological, serological, and culture techniques; phenotypic characterisation; and molecular diagnostics. In this review, we summarize these techniques and identify their merits and pitfalls in the identification of the causative agents of mycetoma and the extent of the disease. We also emphasize the fact that there is no ideal diagnostic tool available to identify the causative agents and that future research should focus on the development of new and reliable diagnostic tools.     

Polymorphisms in genes involved in innate immunity predispose toward mycetoma susceptibility

Madurella mycetomatis is the main causative agent of mycetoma, a tumorous fungal infection characterized by the infiltration of large numbers of neutrophils at the site of infection. In endemic areas the majority of inhabitants have Abs to M. mycetomatis, although only a small proportion of individuals actually develop mycetomal disease. It therefore appears that neutrophils are unable to clear the infection in some individuals. To test this hypothesis, 11 single nucleotide polymorphisms involved in neutrophil function were studied in a population of Sudanese mycetoma patients vs geographically and ethnically matched controls. Significant differences in allele distribution for IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP-4), NO synthase 2 (NOS2), and complement receptor 1 (CR1) were found. Further, the NOS2(Lambaréné) polymorphism was clearly associated with lesion size. The genotypes obtained for CXCL8, its receptor CXCR2, and TSP-4 all predisposed to a higher CXCL8 expression in patients, which was supported by the detection of significantly elevated levels of CXCL8 in patient serum. The NOS2 genotype observed in healthy controls was correlated with an increase in NOS2 expression and higher concentrations of nitrate and nitrite in control serum. We present the first evidence of human genetic predisposition toward susceptibility to mycetoma, a neglected infection of the poor.     

Mycetoma of thumb caused by Nocardia transvalensis

A case of mycetoma of thumb due to Nocardia transvalensis is described. Four earlier isolations of this rarely repoted etiological agent of mycetoma are reviewed. The patient in the present case was successfully treated with cotrimoxazole given orally.     

Mycetoma in China: A Case Report and Review of the Literature

Mycopathologia - Mycetoma is a chronic granulomatous infectious disease that can affect the skin, subcutaneous tissue, fascia and bone. It can be caused by filamentous bacteria or fungi and usually...     

Head and Neck Manifestations of Paracoccidioidomycosis: An Epidemiological Study of 36 Cases in Brazil

Background

Paracoccidioidomycosis is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. It is the principal systemic mycosis in Brazil, with higher incidence rates in the southern, southeastern, and midwestern regions. It primarily involves the lungs, but head and neck manifestations are common, and differential diagnosis with granulomatous and neoplastic diseases should therefore be considered.

Methods

We conducted a retrospective analysis of medical records of paracoccidioidomycosis cases with head and neck manifestations in southern Brazil over a 10-year period, from 1998 to 2008.

Results

A total of 36 cases of paracoccidioidomycosis were confirmed by histopathological examination, fungal investigation, or culture. Most cases consisted of men with smoking and/or chronic drinking habits and with poor hygiene and nutrition.

Conclusions

Paracoccidioidomycosis is endemic to southern Brazil. Most cases with mucocutaneous manifestations affect the head and neck region. Given that risk factors and clinical manifestations are similar to those of head and neck carcinomas, a differential diagnosis has to be done.     

Active Matrix Metalloprotease-9 Is Associated with the Collagen Capsule Surrounding the Madurella mycetomatis Grain in Mycetoma

Madurella mycetomatis is the main causative organism of eumycetoma, a persistent, progressive granulomatous infection. After subcutaneous inoculation M. mycetomatis organizes itself in grains inside a granuloma with excessive collagen accumulation surrounding it. This could be contributing to treatment failure towards currently used antifungal agents. Due to their pivotal role in tissue remodelling, matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) or tissue inhibitor of metalloproteinases (TIMP) might be involved in this process. Local MMP-2 and MMP-9 expression was assessed by immunohistochemistry while absolute serum levels of these enzymes were determined in mycetoma patients and healthy controls by performing ELISAs. The presence of active MMP was determined by gelatin zymography. We found that both MMP-2 and MMP-9 are expressed in the mycetoma lesion, but the absolute MMP-2, -9, and TIMP-1 serum levels did not significantly differ between patients and controls. However, active MMP-9 was found in sera of 36% of M. mycetomatis infected subjects, whereas this active form was absent in sera of controls (P<0.0001). MMP-2, MMP-9, and TIMP-1 polymorphisms in mycetoma patients and healthy controls were determined through PCR-RFLP or sequencing. A higher T allele frequency in TIMP-1 (+372) SNP was observed in male M. mycetomatis mycetoma patients compared to controls. The presence of active MMP-9 in mycetoma patients suggest that MMP-9 is activated or synthesized by inflammatory cells upon M. mycetomatis infection. Inhibiting MMP-9 activity with doxycycline could prevent collagen accumulation in mycetoma, which in its turn might make the fungus more accessible to antifungal agents.