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Chromoblastomycosis is a chronic granulomatous infection of the skin and subcutaneous tissue caused by dematiaceous fungi endemic to tropical and subtropical areas. These melanized fungi invade cutaneous tissue through an inoculation site (usually by traumatic skin penetration when exposed to infected soil), resulting in slow-growing warty plaques and cauliflower-like lesions that may ulcerate. The diagnosis of chromoblastomycosis is usually made by the histopathologic identification of clusters of thick-walled cells in cutaneous tissue (medlar bodies, muriform bodies, or sclerotic bodies). A neglected tropical disease, chromoblastomycosis, can have serious complications (eg, disabling cutaneous fibrosis, secondary infection) that may be irreversible. Recognizing and diagnosing chromoblastomycosis can be challenging, and many infectious and noninfectious etiologies must be excluded. Because chromoblastomycosis is a chronic, indolent condition, treatment is challenging and can include surgical excision for mild cases to long-term oral antifungal medications for moderate-to-severe cases. However, the treatment course is long and may be refractory to treatment, requiring other therapies. Even after treatment is initiated, long-term monitoring is essential to ensure the best patient outcomes and prevent recurrence. This activity describes the epidemiology, microbiology, pathogenesis, clinical presentation, diagnosis, and management of chromoblastomycosis, providing healthcare professionals with the knowledge and tools to improve patient care for this complex condition. Objectives: Identify the clinical features of chromoblastomycosis, recognizing its varied presentations from pink macules to warty plaques and nodules. Differentiate the myriad microbiological characteristics of different fungal strains, understanding their implications for disease severity and treatment. Identify key clinical findings, assess laboratory findings, and review objective information to diagnose chromoblastomycosis. Collaborate with the interprofessional team to educate, treat, and monitor patients with chromoblastomycosis to improve patient outcomes and prevent complications. Access free multiple choice questions on this topic.

Chromoblastomycosis is a chronic granulomatous infection of the skin and subcutaneous tissue caused by several different dematiaceous fungi (ie, fungi containing pigment in the cell wall, whether melanin or melanin-like).[1][2] The indolent infection begins with the cutaneous inoculation of fungi, usually through some portion of the fungal cell capable of reproduction or propagation (eg, conidia, mycelia), into exposed skin, typically due to trauma.[3][4] The infection has wide morphologic variability but typically begins as a pink-to-red macule or papule and evolves in later stages to a verrucous, hyperkeratotic plaque, tumor, or nodule; ultimately, the slow-growing, warty (eg, cauliflower-like) lesions may ulcerate.[2][5] The disease is most common in tropical and subtropical areas, where it is endemic and a neglected tropical disease; as such, it should be most strongly considered in patients who have recently traveled to or originated from these areas.[6] Diagnosis of chromoblastomycosis requires the identification of multicellular clusters of pigmented fungal cells, which produce a characteristic finding called sclerotic bodies (ie, muriform bodies, copper pennies, medlar bodies) on a potassium hydroxide stain or with histopathologic analysis of a skin biopsy.[4] Although other differential diagnoses may include infectious and noninfectious verrucous lesions, the treatment of chromoblastomycosis includes surgical removal for mild disease and antifungal therapy for moderate-to-severe disease.[7] If left untreated, chromoblastomycosis complications can include debilitating tissue fibrosis, squamous cell carcinoma in the site of prior infection, lymphedema, or secondary bacterial infection.[8][9]

Many melanized fungi can cause chromoblastomycosis, but the main causes are usually from 2 genera: Fonsecaea spp (especially F pedrosoi) and Cladophialophora spp (especially C carrionii).[10][11] Demiataceous fungi (ie, phaeoid, black fungi, pigmented) pathogenic to humans include those nonopportunistic organisms that cause chromoblastomycosis and the opportunistic pathogens that cause pheohyphomycosis, the latter of which is more likely associated with internal organ involvement.[12] Important species for chromoblastomycosis include: Fonsecaea spp: F pedrosoi, F monophora, F nubica, F pugnacious, F brasiliensis, F erecta) Cladophialophora spp: C carrionii, C yegresii Exophiala spp: E dermatitidis (formerly Wangiella dermatitidis), E spinifera, E jeanselmei, E alcalophila Phialophora spp: P verrucosa, P americana, P chinensis, P macrospora Rhinocladiella spp:  R similis, R mackenziei, R aquaspersa  [10] [13] [14] [15] [16] These etiologic organisms exist in cutaneous tissue in various yeast-like forms and reproduce through asexual reproduction, though at least 1 species has been shown to reproduce through a cleistothecium-like structure.[13][17] The saprophytic fungi have been isolated from wood, soil, and other plant material in many rural communities, thus implicating their method of entry into the host through trauma and after exposure to plant material.[7][18][7]

Chromoblastomycosis is a disease in the humid, semiarid climates of the tropical and subtropical world.[19] In 1 review of over 2081 patients from South America and the Caribbean, 80.3% were male, and the mean age was 56.1 years.[20] Disease duration was 10.8 years, with lesions mostly on the lower limbs (60%), and the most common presenting symptoms were itching and pain; the most common forms of the lesion at presentation were verrucous (46.4%) or tumorous (21.7%).[20] The most frequent comorbidity in patients with chromoblastomycosis was post-kidney transplantation, though leprosy was a common concomitant infection.[20] Chromoblastomycosis leads to significant disability in agricultural workers in rural areas, particularly as the disease is spread via direct inoculation into the skin from soil or other plant material. However, adult male agricultural workers are most likely to be diagnosed with chromoblastomycosis; the condition has also been reported in children.[20][21] The incidence of chromoblastomycosis is difficult to determine since few studies describe its distribution; however, it is a neglected tropical disease more likely to be found in tropical climates and less likely in areas like the United States.[22] Even in India, chromoblastomycosis represents 1 of the rare fungal infections seen in 1 study in the population.[22] Although underestimated because it is not classified as a notifiable disease to public authorities in many nations, it is reported to be most common in 3 different continents (South America, Africa, and Asia), with higher reported rates in Costa Rica, Dominican Republic, Venezuela, French Guyana, Comoros, Madagascar, and Gabon, among others.[23]

Chromoblastomycosis follows a similar pattern explaining its pathophysiology; namely, after traumatic inoculation from the environment leading to a chronic cutaneous granulomatous and fibrotic reaction, multiple microabscesses with tissue proliferation develop, leading to a T-helper cell type 2 (Th2) immune reaction and the embedding of sclerotic bodies in infected tissue and a polymorphous clinical appearance.[24] After cutaneous inoculation, purportedly following trauma, a dematiaceous fungal species enters the skin and rarely disseminates further.[4] Several days after traumatic implantation, the pigmented fungi differentiate into muriform cells (ie, sclerotic bodies) within phagocytic cells, which explain the fungal globe-shaped, multiseptate morphology.[25][26] The sclerotic bodies—brown septate cells that resemble copper pennies—are extruded transepidermally, ultimately appearing as black dots clinically, a characteristic clinicopathologic correlate on physical examination.[27] During phagocytosis, toll-like receptor dysfunction has been implicated in the host cell's ability to mount an appropriate eradication response, resulting in a granulomatous reaction.[28] Few virulence factors are known in the pathogenesis of chromoblastomycosis, but many elements of organisms that cause chromoblastomycosis have been implicated. Melanin: The presence of melanin has been implicated as a protective mechanism in chromoblastomycosis. Melanin is thought to have unpaired electrons to protect fungal elements from reactive oxygen species produced by macrophages and neutrophils.[29][30] Cell adhesion, invasion, and survival antigens: Some species that cause chromoblastomycosis have been found to contain specific elements to aid in cell adhesion.[31] One study showed that peptide-breaking enzymes of Fonsecaea spp aid in disseminating and invading fungal elements throughout the cutaneous tissue.[32] Other species have been shown to have active phospholipase, allowing easy invasion by lipolysis of the cell membrane and the conversion of arachidonate to prostaglandins (eg, prostaglandin E2), which helps downregulate macrophages, allowing microbial survival.[33][34]

Cell adhesion, invasion, and survival antigens: Some species that cause chromoblastomycosis have been found to contain specific elements to aid in cell adhesion.[31] One study showed that peptide-breaking enzymes of Fonsecaea spp aid in disseminating and invading fungal elements throughout the cutaneous tissue.[32] Other species have been shown to have active phospholipase, allowing easy invasion by lipolysis of the cell membrane and the conversion of arachidonate to prostaglandins (eg, prostaglandin E2), which helps downregulate macrophages, allowing microbial survival.[33][34] Muriform cell architecture: Muriform cells have thicker polyhedral cell walls than the thinner ones of hyphae, which may improve the organism's ability to diminish host response, resulting in fibrous tissue formation; this may be implicated in the chronicity of infection since the fungi can be dormant and proliferate with immune evasion.[35][36] The immune response also plays an important role in propagating chromoblastomycosis infection. Complement proteins involved in opsonization can be activated by some Fonsacaea spp, resulting in chemoattract proteins (eg, C5a) increasing the local inflammatory response.[37] For unclear reasons, neutrophils have specificity in their toll-like receptor types to eliminate conidia or hyphae forms of fungi, suggesting specificity among fungal elements and the immune system for fungal elimination.[38] However, neutrophils and macrophages have limited ability to kill intracellular fungi, even with an oxidative response, likely related to melanin produced by the fungi.[39][30] Organisms causing chromoblastomycosis have been shown to have resistance to microbicidal molecules, impacting the effects of major histocompatibility complex class II, CD80, interleukin-12, and T-helper cell type 1 (Th1) responses.[40][41] Other studies have shown the effect of chromoblastomycosis organisms on interleukin-17, interleukin-10, and Langerhans cells, promoting chronic infection.[42][43][44] Meanwhile, the humoral immune response is poorly understood, and immunoglobulins are not yet known to be involved to a great extent. However, some immunodeficiency syndromes (eg, CARD9 mutations) and genetic associations (eg, HLA-A29 or HLA-B*4802 deletion) have been associated with developing chromoblastomycosis.[45][46][45][47]

Once a skin biopsy is performed for both histopathologic analysis and culture, a microscopic examination reveals the findings below: Pseudoepitheliomatous hyperplasia of the epidermis Irregular acanthosis and hyperkeratosis alternating with atrophy Neutrophilic microabscesses with muriform cells (ie, polyhedral, chestnut-like cells measuring 5-12 μm with longitudinal septa resembling a brick wall) Dermal granulomas with epithelioid cells Increased number of dermal capillaries Variable dermal fibrosis associated with mononuclear cells (eg, histiocytes, plasma cells, lymphocytes)[24] However, the most pertinent finding is the presence of sclerotic bodies (ie, medlar bodies, muriform cells, copper pennies) in the dermis (see Image. Chromomycosis of Skin).[48][49] The tissue between the bodies may show variable levels of fibrosis, depending on the extent and duration of the disease. When ulceration has occurred, there may be a secondary bacterial infection.[27]

Following trauma to the skin, usually in an outdoor environment with exposure to soil or plant material, fungi proliferate in the cutaneous tissue.[50] The evolution of chromoblastomycosis usually starts with a small, pink-to-red macule or papule and can progress to myriad variable morphologic varieties, which depend on the virulence, location, and advancement of the disease; some common morphologies are listed below.[5] Verrucous papule Nodules Scaly plaque Exophytic or ulcerative tumor (ie, cauliflower-like mass) Cicatricial plaques Typically, most lesions are on the lower extremities (see Image. Chromoblastomycosis), and nearly all patients with the disease have had exposure to hot, tropical environments, with the disease progressing in an indolent course, even lasting many weeks before presentation.[5] For this reason, after appreciation of the physical findings, the skin examination should focus on the extent of the disease, the presence of satellite lesions, or the involvement of deeper organs, which is rare and may represent a diagnosis of pheohyphomycosis.[51][52] Lymphatic spread should be evaluated near the existing lesion or lesions.[53] Once the physical examination shows characteristic findings that could indicate chromoblastomycosis, history-taking should emphasize questions intended to rule out other differential diagnoses. Pruritus is a dominant complaint among patients with chromoblastomycosis, with pain at a later time; however, these findings may present late in the clinical course of the disease, particularly in trauma-prone locations.[54] Patients should be asked about: Recent travel to endemic tropical or subtropical areas History of prior surgeries or skin changes in the location (eg, squamous cell carcinoma, keloid) Exposure of skin to trauma or injury previously (eg, gardening) Outdoor recreation (eg, hiking, camping) Occupation (eg, farmer, agricultural worker, outdoor occupations) Exposure of skin to the environment (eg, walking barefoot, exposure to volcanic soil) History of malignancy (eg, mycosis fungoides) History of other infections (eg, bacterial, fungal, protozoan, viral) History of inflammatory diseases that can present with disfiguring skin lesions (eg, lupus, sarcoidosis) Family history of fungal infections Other issues relevant to the history or course of chromoblastomycosis [55][56][57]

History of malignancy (eg, mycosis fungoides) History of other infections (eg, bacterial, fungal, protozoan, viral) History of inflammatory diseases that can present with disfiguring skin lesions (eg, lupus, sarcoidosis) Family history of fungal infections Other issues relevant to the history or course of chromoblastomycosis [55][56][57] The absence of these historical findings should not exclude chromoblastomycosis since patients may not remember the lesions.

The diagnosis of chromoblastomycosis should be suspected in patients who have indolent courses of verrucous papules, nodules, or plaques who are from or have recently traveled to endemic tropical or subtropical areas; however, it has also been found in nonendemic areas.[50][58][50] Dermoscopy may be used to identify black dots on the lesion, resembling "cayenne pepper" spots, which are associated with the transdermal extrusion of sclerotic bodies.[59] Scraping the lesion and applying a potassium hydroxide stain on the glass slide for viewing under a microscope can reveal the presence of copper pennies, the clusters of fungal cells.[2]. However, performing a skin biopsy is most prudent to observe the granulomatous reaction with medlar bodies, the thick-walled pigmented copper bodies in the dermis; either 1 biopsy should be divided for histopathology and culture each, or 2 punch biopsies should be performed.[60] A calcifluor white stain may be used if the fungal elements are challenging to identify since the fluorescent stain binds fungal cell walls when exposed to ultraviolet light.[24][61][62][24] Fungal cultures may be used to identify the genus, in which case an antibiotic may be needed to inhibit bacterial growth, but further molecular testing is needed to identify the species causing chromoblastomycosis.[63] Serologic by immunosorbent assay (eg, enzyme-linked immunosorbent assay [ELISA]) is not commercially available but has been used in research studies.[64][65][66]

Chromoblastomycosis treatment depends on the severity and extent of the disease, including the size of lesions, number of lesions, presence of complications, and prior response to treatment.[26] There are few randomized clinical trials to evaluate treatment success. Generally, mild disease is more amenable to surgical excision, whereas moderate-to-severe disease is best addressed with antifungal therapy.[67][58] Disease severity is classified as follows: Mild: Scales or nodules up to 5 cm in diameter Moderate: Single or multiple lesions in verrucous, tumoral, or plaque forms on 1 or 2 adjacent body areas up to 15 cm in diameter Severe: Single or multiple lesions in extensive areas beyond moderate [26] Mild Disease Mild disease is most appropriately treated with procedural intervention, usually surgical excision with 5-mm margins of healthy tissue, to prevent fungal spread through lymphatic channels.[26] Mohs micrographic surgery or skin grafting can be considered on a case-by-case basis.[68] Other procedural interventions, which may be used with or without oral medications, have included: Photodynamic therapy Long-pulsed 1064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser Carbon dioxide fractional laser Heat therapy (beyond 46 °C for fungicidal activity) Cryosurgery.[69][70][71][72][73] Moderate-to-Severe Disease Antifungal drugs should be initiated for moderate-to-severe disease. The primary recommended treatments are terbinafine and itraconazole, administered on dual oral therapy at 200 to 400 mg/day and 250 to 500 mg/day, respectively.[26] Itraconazole: An azole drug that inhibits fungal 14-α demethylase, treatment with 100 to 200 mg has been used as monotherapy for 12 to 24 months with varying success.[74] Another study showed that 200 to 400 mg of itraconazole needed to be used for up to 30.5 months for the clinical cure of F pedrosoi.[75] However, monotherapy is sometimes avoided for improved efficacy, and instead, terbinafine or 5-fluorocytosine (50-150 mg/kg/day) has been used in conjunction with itraconazole at 100 to 400 mg/kg/day for chromoblastomycosis.[76][77] Pulsed itraconazole at 200 mg daily for 7 days monthly has also been used successfully in patients with chromoblastomycosis.[78]

Itraconazole: An azole drug that inhibits fungal 14-α demethylase, treatment with 100 to 200 mg has been used as monotherapy for 12 to 24 months with varying success.[74] Another study showed that 200 to 400 mg of itraconazole needed to be used for up to 30.5 months for the clinical cure of F pedrosoi.[75] However, monotherapy is sometimes avoided for improved efficacy, and instead, terbinafine or 5-fluorocytosine (50-150 mg/kg/day) has been used in conjunction with itraconazole at 100 to 400 mg/kg/day for chromoblastomycosis.[76][77] Pulsed itraconazole at 200 mg daily for 7 days monthly has also been used successfully in patients with chromoblastomycosis.[78] Amphotericin B: Amphotericin B was shown to be effective when administered locally in chromoblastomycosis lesions; however, the dose may be too high and cause significant adverse effects, including pain, hemolysis, fibrosis, and gangrene.[79][80] Terbinafine: Terbinafine is an allylamine that inhibits squalene epoxidase; it was previously used at 500 mg/kg/day for 6 to 12 months for monotherapy of chromoblastomycosis.[81] Terbinafine is not successful as monotherapy in other studies, but dual therapy with terbinafine and an azole antifungal (eg, itraconazole, voriconazole) is thought to be synergistic.[82][83][84] Posaconazole and voriconazole: Both posaconazole and voriconazole have been used for chromoblastomycosis at 800 mg (as 2 or 4 doses) or 400 mg (as 2 doses), respectively, but these are usually limited to refractory cases or cases in which cost or other medications are an issue.[85][86] Imiquimod: Imiquimod is a toll-like receptor 7 agonist found to significantly improve the lesions of chromoblastomycosis when used with itraconazole with or without terbinafine.[87][88] Glucan: Glucan is a pathogen-associated molecular pattern that was found to improve the treatment of chromoblastomycosis when used at 5 mg/week with itraconazole at 400 mg/day.[89][90] Retinoids: Synthetic retinoids like acitretin have been combined with other medications (eg, imiquimod, itraconazole) for chromoblastomycosis.[91] Melanin Inhibitors: Molecules like tricyclazole, which inhibits melanin, have been thought to help with fungicidal activity in chromoblastomycosis.[92] The use of melanin inhibitors in conjunction with antifungal therapy might be useful to reduce fungal defenses for better antifungal penetration.[93]

Retinoids: Synthetic retinoids like acitretin have been combined with other medications (eg, imiquimod, itraconazole) for chromoblastomycosis.[91] Melanin Inhibitors: Molecules like tricyclazole, which inhibits melanin, have been thought to help with fungicidal activity in chromoblastomycosis.[92] The use of melanin inhibitors in conjunction with antifungal therapy might be useful to reduce fungal defenses for better antifungal penetration.[93] Other medications of interest for fungicidal properties include HIV peptidase inhibitors and ajoene (garlic extract that inhibits phosphatidylcholine biosynthesis).[94] The presence of adverse effects (eg, hepatotoxicity in terbinafine) may change drug choice, and complications of the disease (eg, fibrosis) can affect the availability of the medication in cutaneous tissue. For example, although liver function monitoring may be required for terbinafine, it has fewer drug-drug interactions compared with itraconazole, which may warrant its selection. Because fungi can spread to adjacent healthy skin, monitoring after complete clinical resolution for several months without symptoms is necessary and can include regular skin biopsies with culture and fungal assessments. Regular follow-up should be performed to ensure complete treatment, barring expected atrophic scarring.

The differential diagnosis of chromoblastomycosis should include infectious and noninfectious causes that can appear clinically similar. Infectious causes that appear similar and should be considered include: Fungal: Lobomycosis, Pheohyphomycosis, Eumycetoma, Blastomycosis, Coccidioidomycosis, Sporotrichosis, Majocchi granuloma, Paracoccidiomycosis) Bacterial: Tuberculosis, Actinomycetoma, Botryomycosis, Syphilis, Yaws, Nontuberculous mycobacterial infection Viral: Verruca vulgaris, Papilloma Protozoan: Leishmaniasis, Rhinosporidiosis Helminth: Filariasis Alga: Protothecosis [26] Noninfectious causes should also be considered due to similar clinical appearance or due to complications of chromoblastomycosis, including: Melanoma Squamous cell carcinoma (eg, keratoacanthoma) Keloid Sarcoidosis Podoconiosis Systemic lupus erythematosus [26]

Although treatable, there are many cases refractory to treatment; therefore, early intervention with regular follow-up is essential to reduce morbidity and mortality. Because there is rare internal organ involvement and the disease remains mostly cutaneous, there is less likely to be mortality due to the disease, except in certain cases, such as those with disseminated disease.[26] Without treatment, complications are likely to occur, and with treatment, monitoring must be performed to observe patients for adverse effects of treatment (eg, hepatotoxicity).

The most common complications of chromoblastomycosis include scarring (especially atrophic scarring), disabling tissue fibrosis (which could lead to ectropion or joint immobility), ulceration, secondary bacterial infection, lymphatic spread in a sporotrichoid pattern, and lymphedema resulting in elephantiasis.[9][26] There have been rare, documented cases of malignant transformation of chromoblastomycosis to squamous cell carcinoma and other rare cases of disseminated diseases, though this is unlikely as compared with other dematiaceous fungi.[95][96][97]

Patients should receive significant education on the prevention of chromoblastomycosis. Avoidance of cutaneous trauma in endemic areas is essential, and wearing protective equipment is important if individuals work outdoors or are engaged in outdoor recreation.[26] However, many patients susceptible to chromoblastomycosis live in low-resource settings with high temperatures, so reasonable planning should be discussed with manageable patients. Vaccination studies are limited, and no commercial vaccine exists for chromoblastomycosis.[26] During treatment, patients should be educated on the expected treatment course ( which may be lengthy with multiple treatments) to ensure patient compliance with treatment. Discussion on the myriad adverse effects of treatment medications should be discussed thoroughly, and any drug-drug interactions should be discussed.

Chromoblastomycosis is a rare fungal infection and is best managed by an interprofessional team that includes an infectious disease consultant, surgeon, emergency department physician, wound care nurse, dermatologist, and an internist. Chromoblastomycosis is a chronic granulomatous infection of the skin and subcutaneous tissue caused by several different dematiaceous fungi (brown pigment-producing), resulting in the formation of slow-growing, warty plaques, cauliflower-like lesions that may ulcerate.[98][99][100] The prognosis depends on lesion size and extent. The clinician can excise single small lesions followed by antifungal therapy. Oral antifungal agents alone are an alternative approach if surgery is not feasible or the disease is advanced.[27][101]