The clinical presentation follows the inoculation of fungi on a previously injured skin and the most common sites are the upper and lower extremities [3]. Depending on the stage of disease, lesions that have been described include [3]:

• Nodular - Soft, mildly elevated, dull to pink-colored nodules that possess a smooth surface, either scaly or verrucous. They are most frequently encountered on lower extremities.
• Verrucous - Skin lesions are in the form of warts and hyperkeratosis.
• Tumorous - Nodular forms may eventually progress to large lobulated, papillomatous or cauliflower-like masses covered by crusts and epidermal debris. The border of the foot is the most common site of occurrence.
• Plaques - Developing on the upper parts of the limbs, plaques of various size and shape, either red or violaceous color, may be encountered as well.
• Cicatricial - Lesions are at the level of the skin and are distinguished by peripheral extension and scarring. Cicatricial forms often cover vast areas of the body and are seen in advanced disease

Depending on the stage of the disease, solitary lesions, either plaques or nodules (mild forms), multiple nodular and/or verrucous lesions, together with plaques (moderate form) and extensive involvement of several lesion types (severe form), are encountered [3]. The clinical course starts asymptomatically, while local pain and pruritus that can be intense is reported, as well as burning paresthesias [4]. Severe forms of the diseases are characterized by edema of the extremities because of lymphatic involvement, secondary bacterial infections and ankylosis [3].

• Pain

  The clinical presentation encompasses polymorphic skin lesions and symptoms such as pruritus and paresthesias, as well as pain. [symptoma.com]

  The most common associated symptoms were itching, pain and burning sensation. Mycological examination was positive in 91% of cases and Fonsecaea pedrosoi was the most prevalent etiologic agent. [ncbi.nlm.nih.gov]

  The patient developed a painful nodule at the site on the left elbow (Figure 1). [mdedge.com]

• Outdoor Worker

  The infection usually occurs through traumatic skin inoculation, with the majority of lesions occurring on the feet and legs of outdoor workers. [doi.org]

  The majority of lesions are observed on extremities of outdoor workers [ 1, 12–14 ]. Carrión [ 15 ] and Queiroz-Telles et al. [ 1 ] described f ve types of lesions; nodular, tumorous, verrucose, cicatricial and plague types. [academic.oup.com]

• Rubber Plantation Worker

  The patient, who was a rubber plantation worker in the southern state of Johor, presented to the ENT clinic with a history of epistaxis. He did not recall any history of injury to the nose. [ncbi.nlm.nih.gov]

• Ankylosis

  Severe forms of the diseases are characterized by edema of the extremities because of lymphatic involvement, secondary bacterial infections and ankylosis. [symptoma.com]

  The lesions are also very prone to complications such as bacterial infections, and may also result in lymphoedema (fluid retention and swelling caused by blockage of lymphatic duct) and ankylosis (rigidity of bones of a joint due to the bone tissues sticking [medindia.net]

  In severe cases, lymphedema and ankylosis occur which may alter the clinical appearance. The disease, however, typically remains confined to the subcutaneous fat and does not involve the underlying muscle or bone. [dermatologyadvisor.com]

  In the most severe cases, chronic lymphoedema and ankylosis develop and non-invasive squamous cell carcinomas may arise from chronic lesions 57, 58. [mmy.oxfordjournals.org]

• Foot Deformity

  foot deformity chromoblastomycosis (krōˈ·mō·blaˈ·stō·mī·kōˑ·sis), n fungal infection often appearing along the lymphatic drainage path, characterized by large, wart-like lesions that are small initially but grow over the course of a few weeks to months [medical-dictionary.thefreedictionary.com]

• Skin Lesion

  Cicatricial - Lesions are at the level of the skin and are distinguished by peripheral extension and scarring. [symptoma.com]

  Little is known about opportunistic fungi causing skin lesions in tropical countries such as Panama. [ncbi.nlm.nih.gov]

  Chromoblastomycotic skin lesions particularly atypical ones may be confused with other clinical conditions involving skin and are presented here for their academic interest. [ijhas.in]

• Hyperkeratosis

  Biopsies taken from the periphery of the lesions showed slight laminar hyperkeratosis, as well as pseudocarcinomatous hyperplasia with microabscesses. [doi.org]

  Additional histologic findings are hyperkeratosis, parakeratosis and abundant polymorphonuclear cells with giant cell formation. [symptoma.com]

  Microscopically the skin shows hyperkeratosis and pseudoepitheliomatous hyperplasia and a diffuse chronic inflammatory infiltrate. The organisms are round, golden brown in colour and thick walled. [histopathology-india.net]

  Histologic appearances are hyperkeratosis, pseudoepitheliomatous hyperplasia and granulomas in the upper and mid dermis. The granulomas are mostly of tuberculoid type, although a few suppurative granulomas are present. [odermatol.com]

  In this study hyperkeratosis and parakeratosis were observed, as well as abundant presence of polymorphonu-clear cells and giant cell formation. Muriform cells were easily identified in routine haematoxylin-eosin stain and KOH wet mounts. [academic.oup.com]

• Subcutaneous Nodule

  On inspection, he had a large verrucous mass in the sacral region, and two large subcutaneous nodules in the anterior thoracic wall. He claimed the lesions were several years old. [ncbi.nlm.nih.gov]

  Subcutaneous nodules develop in the nasal and perinasal regions and progressive generalised facial swelling may occur. Infections also occur in horses usually producing extensive nasal polyps and other animals. [mycology.adelaide.edu.au]

  nodule: Disseminated chromoblastomycosis caused by phialophora. 61 Qiu Y...Deng J 31229375 2019 8 Exophiala dermatitidis: Key issues of an opportunistic fungal pathogen. 61 Kirchhoff L...Steinmann J 30887863 2019 9 5-aminolevulinic acid-based photodynamic [malacards.org]

  After the initial nodule, new nodules and verrucous plaques appear, usually after several months or years, with islands or normal skin between them. [dermatologyadvisor.com]

• Pruritus

  The clinical presentation encompasses polymorphic skin lesions and symptoms such as pruritus and paresthesias, as well as pain. [symptoma.com]

  Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus. 1 Lesions usually are localized to the initial area of inoculation, generally a break [mdedge.com]

  The pain and pruritus disappeared at the third week of treatment and lesions started to improve at the beginning of the sixth week of therapy. [doi.org]

  There was history of severe pruritus along with heavy scaling mostly at night for the past 4 years. There was no history of trauma and splinter injury in the affected region. [ijhas.in]

  Due to pruritus, satellite lesions or peripheral expansion of the primary site may develop by autoinoculation. Contiguous lymphatic spread may also occur, as well as lymphatic compromise, which can lead to elephantiasis. [dermatologyadvisor.com]

• Skin Plaque

  It is also known as chromomycosis. chromoblastomycosis very chronic tropical fungal foot infection due to Fonsecaea, Cladosporium and Phialophora species; causing formation of large verrucous skin plaques and characterized by secondary infections and [medical-dictionary.thefreedictionary.com]

• Paresthesia

  The clinical presentation encompasses polymorphic skin lesions and symptoms such as pruritus and paresthesias, as well as pain. [symptoma.com]

  From the central nervous system and peripheral nervous system: ataxia, hearing loss, headaches, paresthesia, parkinsonism, peripheral neuropathy, dizziness, sedation, seizures, loss of a clear perception of reality, hallucinations, psychosis. [drrmed.blogspot.com]

To include CBM in the differential diagnosis, a thorough patient history containing information regarding occupation is necessary. Although this condition is not commonly encountered in clinical practice, direct examination and culture of samples scraped from the lesions should be performed in such skin lesions without hesitation and it is the most important part of workup [3]. Studies have reported that the lesions portrayed as "black dots" are most suitable for examination, as they are filled with fungi that are eliminated through the epithelium [3]. The diagnosis can be obtained by standard potassium hydroxide (KOH) preparations for cultivation and hematoxylin-eosin stain [2]., but biopsy and subsequent histologic examination is preferred, to evade bacterial contamination and determine optimal therapeutic strategies [3]. A pathognomonic feature of CBM is the presence of muriform cell in tissue samples. These cells are round or polyhedral, contain a thick wall, range between 5-12 µm in diameter and contain a dark pigment [3]. Additional histologic findings are hyperkeratosis, parakeratosis and abundant polymorphonuclear cells with giant cell formation [6]. To determine the underlying fungal agent, molecular methods such as PCR are necessary, as serological tests are only useful in selected cases [3].

• Fonsecaea Pedrosoi

  Fonsecaea pedrosoi is the most prevalent aetiological agent of chromoblastomycosis. Fonsecaea monophora is a new species segregated from Fonsecaea pedrosoi. [ncbi.nlm.nih.gov]

• Phialophora Verrucosa

  Chung, Attritional Extensor Tendon Rupture in a Patient with Phialophora Verrucosa Tenosynovitis: Case Report, HAND, 10, 2, (342), (2015). [doi.org]

  It is usually caused by Phialophora verrucosa, Fonsecaea compactum, F. pedrosoi, or Cladosporium carrionii. [medical-dictionary.thefreedictionary.com]

  […] chromoblastomycosis A localized chronic mycosis of the skin and subcutaneous tissues characterized by skin lesions so rough and irregular as to present a cauliflowerlike appearance; caused by dematiaceous fungi such as Phialophora verrucosa, Exophiala [medicine.academic.ru]

  Chromoblastomycosis is a chronic, soft-tissue fungal infection commonly caused by Fonsecaea pedrosoi, Phialophora verrucosa, Cladosporium carrionii, or F. compacta. The infection occurs in tropical or subtropical climates and often in rural areas. [nejm.org]

In milder stages of the disease, where lesions are localized and small in number, various forms of physical therapy, including cryotherapy, topical heat, carbon dioxide laser, as well as surgery, are recommended [3] [5]. Anti-fungal therapy is used when the disease exceeds the capacity of surgical repair and under such circumstances, itraconazole is recommended as first-line therapy [6]. This drug is given in dosages of 200-400 mg per os q24h for 6-12 months [6]. Additional treatment options are terbinafine 500-1000 mg q24h or posaconazole, which may be combined with itraconazole [6]. Various chemotherapeutic agents, such as 5-fluorouracil and 5-fluorocytosine, but also calciferol has been used for treatment [3] [5]. Treatment is stopped only when either histologic, clinical or, mycological criteria have been fulfilled [3]:

• Absence of muriform cells, replacement of active inflammatory cells with chronic and extensive fibrosis.
• Complete healing of skin lesions, as well as disappearance of pain and pruritus.
• Absence of fungal elements on direct microscopy and negative culture.

Histologic and mycological criteria should be confirmed for three consecutive months through monthly examinations, whereas clinical criteria are met after two years of absence of the disease [3].

CBM is difficult to treat, but several factors are important predictors of therapy - The underlying causative agent (F. pedrosoi is more sensitive to anti-fungal therapy than C. carrionii and Phialophora verrucosa), initial choice of therapy (fungicidal vs. fungistatic) and the severity of the disease at diagnosis [3]. Studies have determined that more than 10 years pass from the onset of symptoms to the diagnosis [4]., emphasizing the necessity of early recognition of the disease. Although CBM is restricted to the skin and subcutaneous tissue, rare spread via the lymphatic and hematogenous routes have been documented [15].

The causative agents of CBM belong to the group of subcutaneous mycoses (ascomycotous fungi), the Chaetothyriales [3]., and include Fonsecaea pedrosoi, Fonsecaea monophora, Cladophialophora carrionii, Phialophora verrucosa, and Rhinocladiella aquaspersa [7]. In rare cases, Exophiala spinifera and Phialophora richardsiae were also determined as the potential causes [8] [9]., whereas recent discovery of a strain similar to F. pedrosoi and F. monophora, Fonsecaea nubica, was also described as a causative agent [10].

CBM is an occupational disease of farm laborers, lumberjacks or farm product traders in the tropical and subtropical parts of the world [11]. South Africa and Madagascar are countries in which CBM is most prevalent on the African continent, whereas Mexico, Brazil and Venezuela have highest rates of infection in the Americas [3]. In Brazil, estimated prevalence rates are 1 per 196,000 individuals [4]. Asia (China, Japan, India) and Australia are countries that have reported CBM as well [1]. Additionally, hot and humid climates are favorable for Fonsecaea species and Phialophora verrucosa, while Cladophialophora carrionii proliferate in arid conditions [7]. Unlike many fungal diseases that include an immunocompromised status as a risk factor, CBM is almost exclusively seen in immunocompetent individuals [12]. In terms of gender, the majority of patients are males [2], with the male-to-female ratio between 5:1 and 9:1 [11], presumably due to the occupational mode of disease contraction. Most studies report that the vast majority of patients are adults between 30-50 years [11].

The components of the cell-mediated immune system are considered vital in defense against subcutaneous mycoses, primarily macrophages, cells that possess fungicidal activity after phagocytosis [13]. For macrophages to exert their effects, antigen presentation by dendritic cells (the process that also involves phagocytosis) and a subsequent T-cell mediated immune response is necessary [14]. High index of killing was observed for R. aquaspersa, while certain fungal species, such as F. pedrosoi, C. carrionii and P. verrucosa are able to survive inside macrophages and inhibit their intracellular degradation [13]. In fact, synthesis of nitric oxide (NO), which is essential for microbial killing, is inhibited in the presence of F. pedrosoi, P. verrucosa and C. carrionni, but is intact in the presence of R. aquaspersa [13]. Moreover, the process of phagocytosis was shown to be inhibited by mannan and other substances secreted by the fungus [13]. The reason for different fungicidal activity depending on the present species can be partly explained by studies that have determined different cytokine activity. For example, interleukin-1β was induced by F. pedrosoi and R. aquaspersa, while IL-6 secretion by macrophages was seen in C. carrionii [13]. Across all inflammatory reactions in CBM, the role of tumor necrosis factor α (TNF-α) in generation of an inflammatory response has been well-established [4]. All of these pathological changes trigger localized and eventually systemic symptoms [4].

Perhaps the most important preventive strategy is ensuring proper working conditions for workers exposed to occupational hazards that can predispose to a myriad of infections, including CBM. By avoiding skin injury (as much as it is possible), the chances of infection can be reduced.

Chromoblastomycosis (CBM) is a chronic cutaneous infection caused by a group of melanized fungi, the most common agents being Fonsecaea pedrosoi and Cladophialophora carrionii, but several other species have been established as potential causes. CBM is primarily an occupational disease, as the vast majority of patients are labor workers without adequate clothing and footwear and the pathogenesis of invariably starts with fungal implantation on previously damaged skin from work-related trauma [1]. The presumed mode is either puncture by contaminated thorns or wood splinters [2]. Once the fungus enters the subcutaneous tissues, an extensive granulomatous and purulent inflammatory response is observed [1]., leading to several types of skin lesions: plaques, verrucous, tumor-like, nodular and cicatricial [3]. Skin lesions most commonly appear on the extremities, either the arms or legs, but any site on the body may be affected [3]. Main symptoms include intense pruritus, localized pain and paresthesias, but more severe cases present with lymphedema, secondary bacterial infections and ankylosis [4]. To make the diagnosis, it is necessary to perform a full body examination and obtain a proper patient history that will identify the source of the infection and its entry. High index of clinical suspicion should be supported by biopsy or scraping of the lesion for histologic examination and cultivation in specific fungal media, respectively. The hallmark of CBM is the presence of dark-pigmented muriform cells that are embedded in the granulomatous and suppurative tissue, which appear as a result of hyphae accumulation [3]. Once the diagnosis is confirmed, the severity of the disease determines treatment strategy, ranging from physical therapy through surgical resection, carbon dioxide laser, cryotherapy and heat application in localized disease, to chemotherapy and use of anti-fungals in severe forms of the disease [3] [5]. 5-fluorouracil and 5-fluorocytosine, as well as itraconazole, amphotericin B, posaconazole and terbinafine are used either as single agents or in combination [3] [6]., but CBM is often tough to treat due to its frequent resistance to therapy. Reports have determined that as long as 10 years pass from the onset of symptoms to the diagnosis [4]. For these reasons, an early diagnosis may provide significant benefit in terms of treatment success.

Chromoblastomycosis (CBM) is a fungal infection of the skin and subcutaneous tissue restricted to the subtropical and tropical areas of the world, where fungal species that are responsible for CBM proliferate the most. Brazil, Mexico, Venezuela, Madagascar, South Africa India and China are countries that report the highest number of cases. CBM is primarily an occupational disease of farmers, lumberjacks and other field-related jobs, because the fungi establish an infection through previously injured skin by either thorn punctures or wood splinters. CBM is much more frequently seen in males, with an almost 9:1 male-to-female ratio. Once the fungus is introduced into the subcutaneous tissue, the immune system recognizes the threat and attempts to kill the fungus through the activity of macrophages, which "ingest" the fungal particles and try to break them down. Some fungi are able to survive this process and cause an intense inflammatory reaction that triggers symptoms such as pain, severe itch and a tingling sensation due to damage of the superficial nerves. Various skin lesions, depending on the severity of the disease, may be seen and it is imperative to obtain a detailed patient history with an emphasis on the onset of lesions and their progression. To make the diagnosis, however, it is necessary to obtain a sample from the affected skin and examine it by either cultivating in specific fungal media or microscopic examination, since a characteristic cellular type is identified in this infection. Once the diagnosis is made, treatment principles depend on the severity of the disease and extent of skin lesions. Surgery or various forms of physical therapy, including carbon dioxide laser, cryotherapy and application of heat are recommended in localized forms, while anti-fungal drugs and chemotherapeutic agents are indicated in severe forms of the disease. Itraconazole, posaconazole and terbinafine are usually given for several months and cessation of treatment may be performed when there are no signs of fungi in the skin that has completely healed and when clinical symptoms are absent for at least two years. CBM may be hard to treat because resistance to anti-fungal therapy is not uncommon, particularly in severe forms of the disease. One of the most important strategies in reducing the global burden of this infection is a timely diagnosis, since studies have determined that more than a decade passes from the onset of symptoms to the diagnosis, which strengthens the need for high index of clinical suspicion in patients who are living in endemic areas with known occupational risks.

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