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The global burden of chromoblastomycosis

['Daniel Wagner C. L. Santos', 'Special Mycology Laboratory Lemi', 'Division Of Infectious Diseases', 'Federal University Of São Paulo', 'São Paulo', 'Sp', 'Conceição De Maria Pedrozo E Silva De Azevedo', 'Department Of Medicine', 'Federal University Of Maranhão', 'São Luís']

Date: 2021-09

Abstract Background Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease (NTD) and mainly affects populations living in poverty with significant morbidity, including stigma and discrimination. Methods and findings In order to estimate the global burden of CBM, we retrospectively reviewed the published literature from 1914 to 2020. Over the 106-year period, a total of 7,740 patients with CBM were identified on all continents except Antarctica. Most of the cases were reported from South America (2,619 cases), followed by Africa (1,875 cases), Central America and Mexico (1,628 cases), Asia (1,390 cases), Oceania (168 cases), Europe (35 cases), and USA and Canada (25 cases). We described 4,022 (81.7%) male and 896 (18.3%) female patients, with the median age of 52.5 years. The average time between the onset of the first lesion and CBM diagnosis was 9.2 years (range between 1 month to 50 years). The main sites involved were the lower limbs (56.7%), followed by the upper limbs (19.9%), head and neck (2.9%), and trunk (2.4%). Itching and pain were reported by 21.5% and 11%, respectively. Malignant transformation was described in 22 cases. A total of 3,817 fungal isolates were cultured, being 3,089 (80.9%) Fonsecaea spp., 552 (14.5%) Cladophialophora spp., and 56 Phialophora spp. (1.5%). Conclusions and significance This review represents our current knowledge on the burden of CBM world-wide. The global incidence remains unclear and local epidemiological studies are required to improve these data, especially in Africa, Asia, and Latin America. The recognition of CBM as NTD emphasizes the need for public health efforts to promote support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients.

Author summary Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease and mainly affect populations living in poverty with significant morbidity, including stigma and discrimination. The global incidence of CBM remains unclear because this mycosis is not a mandatory notifiable disease and most of the literature consists of case reports or small series incompletely characterized. Although several authors suggest that the CBM global burden may be comparable to mycetoma, its geographic distribution and incidence rates in different endemic areas have never been widely characterized in the medical literature. We retrospectively conducted a comprehensive systematic review of all medical literature published between 1914 and 2020 to better characterize the prevalence rates, geographic distribution, and clinical aspects of CBM in all continents. All reviewed data were not a substitute for high quality epidemiological study or comprehensive surveillance but do provide an approximation of the burden by country. Information generated corroborate the WHO recognition of CBM as a NTD and provides helpful support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients with CBM.

Citation: Santos DWCL, de Azevedo CdMPeS, Vicente VA, Queiroz-Telles F, Rodrigues AM, de Hoog GS, et al. (2021) The global burden of chromoblastomycosis. PLoS Negl Trop Dis 15(8): e0009611. https://doi.org/10.1371/journal.pntd.0009611 Editor: Roderick Hay, International Foundation for Dermatology, London, United Kingdom, UNITED KINGDOM Received: April 6, 2021; Accepted: June 30, 2021; Published: August 12, 2021 Copyright: © 2021 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist.

Introduction Chromoblastomycosis (CBM), together with mycetoma, represents one of the primary implantation mycoses caused by melanized or black fungi widely found in nature that may infect agricultural workers after transcutaneous inoculation during their daily activities [1–4]. Chromoblastomycosis is primarily an occupational disease associated with a considerable social stigma and severe personal and family socioeconomic consequences [1,3,5,6]. It is mainly caused by Fonsecaea spp., followed by Cladophialophora, Phialophora, and Rhinocladiella. The genera Fonsecaea includes three closely related siblings represented by F. pedrosoi, F. monophora, and F. nubica. The genus Cladophilophora spp. contains two related siblings: C. carrionii that may be found in clinical samples and nature, whereas C. yegresii is exclusively found in the environment [1,7–12]. These agents present some peculiarities in terms of geographic distribution and ecological niches. The clinical manifestations and therapeutic response of the patients differs by infecting fungus. CBM is nowadays characterized as a Neglected Tropical Disease (NTD) because (a) it mainly affects populations living in poverty causing significant morbidity and mortality–including stigma and discrimination; (b) it is mostly found in tropical and sub-tropical areas; (c) it may be controlled or eradicated by applying one or more of the five public health strategies adopted by the Department for Control of NTDs; (d) it has been neglected by research when it comes to developing new diagnostics, medicines, and other control tools [1,3–5]. The process of recognizing CBM as NTD began at the meeting held in São Luís, state of Maranhão, Brazil, in 2011, when the disease’s centenary was celebrated. After an application by the Global Action Fund for Fungal Infections with support from the governments of Brazil and Madagascar, World Health Organization (WHO) incorporated CBM into the NTD portfolio in category B in 2017, together with mycetoma and other deep mycoses [1,7]. In most endemic areas, health services do not have professionals trained in the early diagnosis and clinical management of CBM. Skills in skin biopsy, direct microscopy, histopathology with fingal stains fungal culture is often lacking. Effective antifungal treatment rarely included in universal health coverage and government insurance. Long term itraconazole at 400mg daily or variable terbinafine dose are not be available in many countries and is expensive and requires monitoring [1,3,6–9]. Patients are usually diagnosed after several years of clinical manifestations, and medication is unavailable or unaffordable, two factors that may increase the risk of sequelae and further social stigma [1,3]. In addition, CBM in some patients is complicated by continuous bacterial co-infection and later neoplastic transformation of the CBM lesions into epidermoid carcinoma may occur [1,3] The global incidence of CBM remains unclear. Only a few population epidemiology studies have been done. This mycosis is not a mandatory notifiable disease and most of the literature consists of case reports or small series incompletely characterized. Although several authors suggest that the CBM global burden may be comparable to mycetoma, its geographic distribution and incidence rates in different endemic areas have never been widely characterized in the medical literature. We conducted a comprehensive systematic review of all medical literature published between 1914 and 2020 to characterize better the prevalence rates and geographic distribution of CBM in all continents. Data generated in this paper corroborate the WHO recognition of CBM as a NTD and provides helpful support for all local governments interested in developing specific policies and actions for preventing, diagnosing, and assisting patients with CBM [1,5–7,13,14].

Methods Our plan for literature review included the selection of all articles addressing the epidemiology of chromoblastomycosis in the world that were published in four different languages (English, Spanish, French and Portuguese) between 1914 and 2020 and listed in the PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) and Bireme (http://portal.revistas.bvs.br/) with access to "LILACS", "IBECS", "MEDLINE", "Cochrane Library" and "SciELO” databases. The terms used to select papers included "chromoblastomycosis", "chromomycosis", "neglected mycoses", "subcutaneous mycoses" or "implantation fungal infections". Letters to the editor and abstracts available published in congress or conferences were also searched and identified. The literature review was complemented by reviewing the reference lists of all studies selected to be sure that we did not miss any relevant references. Due to the large number of single case reports published in some highly endemic countries, papers from Mexico, Brazil, Venezuela, Colombia, Madagascar, India, China, Japan, and Australia were only included if they reported at least 5 patients. Review papers were selected only to find references to original papers to avoid case duplication [2,15]. All papers in this comprehensive review were able to meet the main diagnostic criteria of CBM: presence of dark pigmented and thick-walled muriform cells in a biological sample. Whenever there was doubt about this finding, the paper was excluded from the analysis. Epidemiological and clinical data of all cases of CBM were collected using a standard clinical form. The variables that were systematically assessed along the literature review included year and country of publication, the number of cases, the period of cases collection, age, gender, history of cutaneous trauma and previous agricultural work, time from onset of symptoms to diagnosis (years), symptoms, clinical pattern of the lesions and severity of the disease, malignant transformation and clinical management (physical methods such as surgery, thermotherapy, laser therapy, and photodynamic therapy; antifungal drugs with itraconazole, terbinafine, iodide, flucytosine) [1,3]. To determine the prevalence rate of CBM in each country, we used the method described by Van de Sande [2]. The number of reported cases along each year in all countries was divided by the total population of each country in the selected period. Population data for each country in each collection period was extracted from the website www.indexmundi.com/facts/indicators/SP.POP.TOTL/compare#country=ma) [2]. As an example 71 cases of CBM were reported between 1978 and 1993 in Sri Lanka, with a mean of 4.73 cases/year. The average population of this country in this period was 16,283,921 inhabitants. In this case, the prevalence of CBM in Sri Lanka was defined as 0.29 cases per 1 million inhabitants.

Discussion The true burden of CBM is not known. A lack of national surveillance systems checking for CBM in sentinel centers does not exist [1,2,232,233]. This paper represents the most comprehensive review of CBM cases published between 1914 and 2020, providing data to partially characterize the relative burden of this neglected implantation mycosis in different countries and the main clinical and mycological characteristics of the affected patients. Our review showed that CBM has been widely described on all continents over the last eight decades and thrives in areas where access to adequate sanitation, clean water, and healthcare is limited. Regardless of the country considered, CBM is diagnosed in people who live in remote and rural areas and affects some of the world’s poorest and most marginalized communities, predominantly in Africa, Asia, and America [1,2,232]. Rural areas in developing countries highly endemic for CBM generally present high informal employment arrangements, low human development index, and lack of appropriate social protection systems for agriculture workers. In most countries, surveillance practices for personal protective equipment (PPE) in agriculture are unknown, and their use in rural areas is woefully inadequate and requires more attention. The lack of protective shoes, gloves, or garments associated with poor hygienic habits and insufficient nutrition may favor development of CBM after infection by implantation [1–7,14,234–236]. It is not known if there are other factors affecting the development of CBM in particular individuals or disease expression and severity. For example, an inability of toll like receptor 7 (TLR7) to recognize and respond appropriately to the causative fungi could underly the progressive nature of CBM in some patients [237]. Although the route of acquisition of CBM agents is by traumatic inoculation, most of the series did not track the source of infection once clinical manifestations as several years usually elapse after trauma when the patients and the lesion(s) grows very slowly. We were not capable to analyze data related to trauma or characterization of rural jobs as this information were not available in most papers [1,3,6,18,19,27,35,56,70,116,165,238,239]. Rarely CBM is described simultaneously with other NTDs (mycetoma, leprosy, filariasis and leishmaniasis). This occurrence reflects areas of co-endemicity, with common environmental exposure in populations under conditions of poverty [1,3,54,56,57,60,108,121]. Although the diagnosis of CBM does not rely on expensive and sophisticated laboratory tools, the disease remains neglected by all health systems, making the time of diagnosis too long (mean of 9 years). This aspect certainly impacts in morbidity, including disease progression, risk of superinfection and malignant transformation [8,56,68,99,167,175,240,241,242]. Considering the insidious progression of the fungal disease, patients continue their labor and social activities for many years before having the diagnosis made [1,3,5,48,176]. Notably, the disease is mostly observed in males probably due to different environmental exposition and possible protection of women by endogenous steroids [1,5]. This hypothesis needs further investigation and validation. However, in some countries the prevalence in women is high probably due to their involvement in agricultural activities [16,43,44,116,122,166–168,199]. Lower limbs are the most common site affected, although some countries frequently reported lesions in upper limbs due to local practice of carrying wood or other agricultural materials in arms or shoulders [16,19,20,165,180,182,204,205,228,229]. In the present review, we adopted the CBM Carrión classification for skin lesions considered the most consistent and comprehensive description of dermatological lesions with updated nomenclature [1,3,65,68]. As expected, warty lesions (29%), tumors (27%), infiltrative plaques (23%), and nodules (12%) were the most common pattern of CBM, but polymorphic lesions may also be found, especially in patients with a long history and chronic evolution of the process [52,56,65,67,68,99,165,169,175]. The main symptoms were itching (21%) and pain (11%), with local edema rarely reported by most authors [6,7,9,21,28,30]. Of note, the pattern of skin lesions is not linked to the etiological agent of CBM. Some series have shown that secondary bacterial infections and lymphedema are concerns. Uncommonly, malignant transformation may occur, especially in patients with a long history of CBM diagnosis [1,3,54,67,68,76,99,103,116,119,167,240–242]. CBM progresses slowly, produces fibrotic changes and lymphatic stasis. Secondary recurrent bacterial infection exacerbates the involvement of lymphatic vessels, resembling elephantiasis. Severe forms of CBM disable and disfigure patients much more frequently than they kill, and are multifactorial [243,244]. Affected people live decades with disability, stigma and social withdrawal. Disability Adjusted Life-Years (DALY) lost due to CBM has not been comprehensively evaluated in endemic areas [1,3–5,7,14,15]. Laboratory diagnosis of CBM requires only the visualization of single or clustered muriform cells by direct mycological examination or histopathology. Most diagnoses in North American and European countries are provided by histological examination. In contrast, in Asian, African, and Latin American countries where CBM is endemic, less than 30% of all cases required biopsy for the diagnosis [8,16,25,49,51,56,68,99,169]. Direct mycological examination with potassium hydroxide solution of skin scrapings containing crusts or cellular debris is a fast and straightforward tool frequently useful in low-income countries to diagnose patients with CBM [56,68,99,170]. Although the different agents of CBM have certain ecological features, there is no apparent impact of the diversity of species on clinical manifestations or therapeutic management. Molecular characterization of different species has mostly been used to characterize this ecology and epidemiological aspects of the various etiological agents of CBM [1,11–13,238,239]. Fonsecaea spp. is the main genus causing CBM worldwide [16,18–25,50–56,68,99,116,165,169,170,189–191]. Molecular studies showed that Fonsecaea pedrosoi is the main species within this genera, and it is found practically in all countries where CBM has been reported. This species causes almost exclusively subcutaneous disease, with rare visceral involvement [11,12,16,68]. Disseminated forms of the disease have also been reported but without unambiguous muriform cells in tissue (44), and thus, they may be considered phaeohyphomycosis. Fonsecaea monophora is widely distributed, with high prevalence, especially in Asia and subtropical or temperate countries. F. monophora, together with F. pugnacius, can cause disseminated CBM or phaeohyphomycosis with visceral impairment [165,245,246]. Finally, Fonsecaea nubica is also widely distributed in Asia, but current studies showed that Madagascar might be the country with the highest number of CBM caused by this species [239]. The second main etiological agent of CBM is C. carrionii, with Venezuela, Madagascar, Australia, India, and China the countries most affected [44,45,48,49,99,165,170,203–208]. This agent is typically found in arid and semi-arid climates, with average yearly temperatures of 24°C, scarce rainfall (up to 600 annual mL) and is located at moderate altitude (up to 500 m) [43,48,99,208]. Finally, Phialophora spp. (P. verrucosa) is an uncommon agent, responsible for almost 30% of cases in the USA [166–170,219–221,228,230]. Rhinocladiella spp. is the etiologic agent of less than 1% of CBM cases [16,68,212]. Treatment of CBM is difficult, and several different therapeutic regimens have been tried, including physical methods. Most of small initial lesions in mild disease can be excised surgically, but clinical data and follow-up of these patients are incompletely characterized. CBM lesions are refractory, and healing is almost impossible to achieve, especially in its moderate to severe clinical presentations [19,21,22,30,52,95,99]. Although there are no randomized clinical trials to define the best choice for its treatment, itraconazole is the main antifungal drug used, specially 400 mg per day in moderate and severe cases, based on observational studies [65,66,68]. Terbinafine is the second most frequently used antifungal drug, specially in some countries as Madagascar and China, based on open and non-comparative clinical trials [163,240]. Voriconazole, posaconazole, and isavuconazole are used only in refractory disease [1,247,248]. Interestingly, some therapies have been abandoned, such as cholecalciferol, thiabendazole, intravenous amphotericin, ketoconazole, and topical 5-fluorouracil. Due to the low cost, potassium iodide has been used in some countries, especially in Cuba and India [19,23,170]. Adjuvant therapy for improve the cellular immune response with topical imiquimod or intramuscular glucan was used mostly in more severe and refractory cases [249–251].

Conclusions Despite all limitations, our study provides a comprehensive review of clinical and therapeutic aspects of CBM and an estimate of the prevalence of the disease in each country. Our maps have shown CBM to be widespread in five different continents, specially in Latin America, Africa and Asia. Countries such as Madagascar, Gabon, Indian Ocean Islands (Comoro and Reunion), Costa Rica, Dominican Republic, Venezuela, French Guiane, and Island of Oceania (New Caledonia) are the countries with the highest incidence densities in the world. CBM in world is probably more common than expected. The disease especially affects men (81.7%), with an average delay of 9.2 years between onset and diagnosis. The mean age was 57.1 years (range 2–93 years), being the lower and upper limbs the most compromised sites. Verrucous, tumoral and plaque represent the main dermatological patterns. Fonsecaea spp. is the main etiological agent, being widely distributed on all continentes and responsible for more than 80% of cases. This review allows the understanding of a gap in epidemiological, diagnostic and therapeutic data. There is an urgent need to create and implement social protection policies for vulnerable populations and national programs for the diagnosis and treatment of the disease.

Supporting information S1 Table. Rate of occurrence, clinical and demographic data of chromoblastomycosis cases stratified by countries. https://doi.org/10.1371/journal.pntd.0009611.s001 (DOCX)

Acknowledgments We thank all the Brazilian Network of Melanized Fungal Infections and the Working Group of Chromoblastomycosis of ISHAM for the encouragement in the development of this work.

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