Continuing Medical Education 495

495
s
Chromoblastomycosis: an etiological, epidemiological, clinical,
diagnostic, and treatment update*

Arival Cardoso de Brito1,2,3, Maraya de Jesus Semblano Bittencourt1

DOI: http://dx.doi.org/10.1590/abd1806-4841.20187321

Abstract: Chromoblastomycosis is a chronic, granulomatous, suppurative mycosis of the skin and subcutaneous tissue caused by
traumatic inoculation of dematiaceous fungi of the family Herpotrichiellaceae. The species Fonsecaea pedrosoi and Cladophialophora
carrionii are prevalent in regions where the disease is endemic. Chromoblastomycosis lesions are polymorphous: verrucous,
nodular, tumoral, plaque-like, and atrophic. It is an occupational disease that predominates in tropical and subtropical regions,
but there have been several reports of cases in temperate regions. The disease mainly affects current or former farm workers,
mostly males, and often leaving disabling sequelae. This mycosis is still a therapeutic challenge due to frequent recurrence of
lesions. Patients with extensive lesions require a combination of pharmacological and physical therapies. The article provides
an update of epidemiological, clinical, diagnostic, and therapeutic features.
Keywords: Chromoblastomycosis; Diagnosis; Diagnostic tests, routine; Epidemiology; Fungi; Therapeutics; Treatment
outcome

INTRODUCTION HISTORY
Chromoblastomycosis (CBM) is a chronic, granulomatous In 1922, Terra et al. coined the term chromoblastomycosis
mycosis of the skin and subcutaneous tissue produced by the trau- to refer to the disease.3 Seventy years later, in 1992, the term was
matic inoculation of various dematiaceous fungi of the order Chae- proposed by the International Society for Human and Animal My-
tothyriales and family Herpotrichiellaceae, present in soil, plants, and cology (ISHAM) as the official name for the mycosis from that pub-
decomposing wood, prevalent in tropical and subtropical regions lication forward.4 McGinnis, in 1983, finalized the long controversy
of the world.1,2 CBM is a progressive, disabling, difficult-to-treat oc- over the nomenclature for the mycosis with the publication in which
cupational disease, evolving with episodes of secondary bacterial he clearly established the concept of chromoblastomycosis, differ-
infections, leading to low work productivity and frequent absentee- entiating it from phaeohyphomycosis and other infections caused
ism. The synonyms for this mycosis vary widely, including: chro- by fungi of the family Herpotrichiellaceae (order Chaetothyriales).1
momycosis, verrucous dermatitis, Lane-Pedroso’s mycosis, Fonse- CBM is currently classified by the International Classification of
ca’s disease, Carrión’s mycosis, cladosporiosis, figueira, formigueiro, Diseases as follows: ICD-9 117.2 and ICD 10-B43.5
blastomycosis nigra, sunda, susna, and chapa, among others.

Received 08 June 2017.

Accepted 24 September 2017.
* Work conducted at the Dermatology Service, Universidade Federal do Pará, Belém (PA), Brazil.
Financial support: None.
Conflict of interest: None.

1
Dermatology Course, Universidade Federal do Pará, Belém (PA), Brazil.

2
Medical Residency in Dermatology, Universidade Federal do Pará, Belém (PA), Brazil.

3
Dermatopathology Laboratory, Universidade Federal do Pará, Belém (PA), Brazil.

Corresponding author:
Maraya de Jesus Semblano Bittencourt
E-mail: [email protected]

©2018 by Anais Brasileiros de Dermatologia

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496 Brito AC, Bittencourt MJS

The first cases of CBM were observed by Pedroso and Gomes melanin complex by interacting with proteins, lipids, and carbohy-
in 1911, but it was not until 1920 that the authors published the four drates from the cell wall and represents an important factor in the
cases which they reported as having been caused by Phialophora ver- virulence of these fungi.37
rucosa.6 However, Brumpt7 contended that the fungus belonged to
a different species, which he named Hormodendrum pedrosoi, later EPIDEMIOLOGY
renamed Fonsecaea pedrosoi by Negroni.8 According to Castro and CBM is a cosmopolitan disease, with the highest prevalence
Castro9, , the first author to publish was a German physician Max in tropical and subtropical regions between 30° latitude North and
Rudolph10, who lived in Brazil, and who in 1914 published six cases 30° latitude South.38 The largest focus of CBM in the world is in
of CBM observed in the town of Estrela do Sul, Minas Gerais State. Madagascar, Africa.39 However, the mycosis displays variable inci-
Rudolph emphasized the disease’s clinical characteristics, and in dence in South America, Central America, North America, Asia, and
four of the six cases he cultured and isolated a brownish-black fun- Europe. Among the countries with temperate climates, there have
gus which he inoculated in animals. There is no record of a histopa- been reports in Russia, Canada, Finland, Czech Republic, Romania,
thology report. In 1915, Medlar11 and Lane12 described the first cases and Poland, in addition to high incidence in Japan.17,40-45
of CBM in the United States. Thaxter isolated and classified the fun- In Venezuela, C. carrionii predominates in the arid states
gus from these cases, calling it Phialophora verrucosa. of Lara and Falcón, while F. pedrosoi predominates in humid ar-
In 1928, Hoffman reported ten cases of a disease similar to eas.20,23,27,28,46 The mycosis occurs in most states of Brazil, the coun-
CBM observed by Guiteras in Cuba in 1908, but not published.13 try with the second largest case series, and where the state of Pará
The first case outside of the Americas was described by Montpellier has the highest prevalence.23,28,30,47,48 Current or former agricultural
and Catanei in 1927 in an Algerian patient.14 The second case in the workers, miners, and woodsmen, predominantly males 20 to 60
United States was reported by Wilson et al. in 1933.15 In 1935, as the years of age, account for 90% of the cases. There is no ethnic predi-
name “chromoblastomycosis” suggested that the etiological agents lection. In Japan, the lesions predominate on the upper limbs, face,
display budding yeasts in the tissue, Moore and Almeida (1935) pro- and neck.44,45 There is no record of direct human-to-human or ani-
posed the term “chromomycosis” to replace “chromoblastomyco- mal-to-human transmission.20
sis”.16 More cases were reported in European countries.17 The fungus
Acrotheca aquaspersa, later Rhinocladiella aquaspersa, was described in PATHOGENESIS
1972 by Borelli.18 The etiological agents of this mycosis, generally with low
The World Health Organization (WHO) keeps a long list of pathogenic power, live as saprophytes in the soil, plants, and organ-
neglected diseases, which is defined as endemic tropical and sub- ic matter in decomposition. Connant in 1937 demonstrated for the
tropical diseases in low-income populations that cause thousands first time that the agents of CBM exist in nature, by isolating fungus
of deaths a year. The list includes diseases caused by infectious Cadophora Americana (later renamed P. verrucosa) from wood.49 Vari-
and parasitic agents (fungi, viruses, bacteria, protozoans, and hel- ous subsequent studies confirmed the etiological agents’ presence in
minths). In Brazil, the neglected diseases include deep mycoses the environment.50-54 CBM results from the transcutaneous, traumat-
such as CMB, paracoccidioidomycosis, Jorge Lobo’s disease, myce- ic inoculation of propagules from various species of dematiaceous
tomas, sporotrichosis, and others.5 fungi. In the host, the propagules adapt to the tissue environment
through the dimorphism of the filamentous phase in globe-shaped
ETIOLOGY structures called muriform cells.
The etiological agents of CBM belong to the order Chaeto- The immune response in CBM is not totally clear, although
thyriales, family Herpotrichiellaceae, and include: Fonsecaea pedrosoi, the main response is cellular, involving macrophages, Langerhans
Fonsecaea monophora, Cladophialophora carrionii, Fonsecaea nubica, cells, factor XIIIa+ dermal dendrocytes, in addition to the humor-
Phialophora verrucosa, Fonsecaea pugnacius, Rhinocladiella aquaspersa, al response. In 2003, D’Ávila et al. analyzed CBM-spectrum dis-
Cladophialophora samoensis, Cyphellophora ludoviensis, Rhinocladiella ease, relating the clinical forms to the cytokine profile.55 Verrucous
tropicalis, and Rhinocladiella similis.1,5,11,12,18-25 Studies on the ribosomal lesions presented parasite-rich granulomas and predominance of
DNA (rDNA) internal transcribed spacer showed that Fonsecaea pe- IL4 and IL10, a Th2 response. In the atrophic forms, they observed
drosoi and Fonsecaea compacta are identical species.26 well-formed granulomas with more epithelioid and Langhans cells,
The most prevalent species (90%) is F. pedrosoi.19,20,27-30 Cases IFN-gamma, and TNF-alpha, a Th1 response profile.
of CBM caused by Exophiala jeanselmei and Exophiala spinifera have Souza et al. (2008) observed that the monocytes of patients
been reported in the literature.31-34 In Panama (2007), there is a report with a severe form of the disease showed increased production of
of CBM caused by Chaetomium funicola.35 IL-10 and lower expression of HLA-DR and costimulatory mole-
In the tissues, the fungi display a micromorphology of cules.56 According to the authors, immune modulation with recom-
round/oval, brownish, thick-walled cells 4-12 microns in diameter, binant IL-12 or anti-IL10 can restore the Th1 immune response in
which multiply by septation in two distinct planes, called muriform these patients.56
(sclerotic) bodies (cells) or Medlar’s bodies, representing the inva- Some studies have addressed macrophage activation and
sive form. The term muriform is preferred to sclerotic, according to destruction of F. pedrosoi, but there is also in vitro evidence that the
Matsumoto.36 The melanin from the dematiaceous fungi is formed fungus can reduce the efficacy of macrophages, with inhibition of
by the polymer dihydroxy naphthalene (DHN), which forms the the immune response and fungal persistence in the tissues.57-59

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Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment update 497

Sotto et al. investigated the cellular immune response, espe- The initial lesion is usually on exposed areas, at the infection site, as
cially antigen distribution in patients’ biopsy specimens.60 In their a papule with centrifugal growth that evolves to any one of the se-
study, the majority of antigens were observed in the cytoplasm of veral clinical forms. The polymorphism of CBM lesions encouraged
the macrophages, and to a lesser extent in the Langerhans cells and some authors to develop various classifications of the clinical forms,
factor XIIIa- positive dendrocytes.60 most of which no longer used, while the classification proposed by
Gimenes et al. demonstrated that patients with the severe Carrión in 1950 (Chart 1) is still in use.65
form of CBM produce high levels of IL-10 and low levels of IFN-γ, The initial lesion may remain circumscribed to the inocula-
together with inefficient T-cell proliferation.61 Meanwhile, patients tion site for months or years, but it usually evolves to one of the le-
with the mild form show intense production of IFN-γ, low levels sion types characterizing the clinical polymorphism of CBM (Figure
of IL-10, and efficient T-cell proliferation. The interaction of conidia 1). By contiguity or lymphatic or hematogenous dissemination, me-
or sclerotic F. pedrosoi cells with Langerhans cells with decreased tastatic lesions appear at other anatomic sites. In the nodular type,
expression of CD40 and B7-2 and immune function inhibition was the clinical expression is that of fibrotic, erythematous-violaceous
demonstrated by Silva et al.62 The immunohistochemical analysis of nodules with a smooth or hyperkeratotic surface (Figure 2). The ver-
23 biopsies from the untreated verrucous form of CBM evidenced rucous type – with a higher prevalence, is characterized by lesions
local immune response with high IL-17 expression and low expres- with a cauliflower appearance, dry, hyperkeratotic, with black dots,
sion of other cytokines, but this Treg/Th17 imbalance can provide usually with abundant CBM agents, but ulceration occurs relatively
proof of decreased immune response to the fungus.63 frequently in this type of lesion (Figure 3). The plaque type displays
Siqueira et al. showed that the hyphae and muriform cells erythematous or violaceous, infiltrated, circumscribed, irregular
are capable of establishing murine CBM with skin lesions and sim- plaques, with sharp, elevated edges and black dots, in some cases
ilar histopathological features to those found in human tissue, and with central scarring (Figure 4). The tumoral type is characterized
that the muriform cells are the most persistent fungal form, while by lobulated single or coalescent tumoral lesions with a smooth or
the mice infected with conidia do not reach the chronic phase of crusted/scaly surface, or a vegetative appearance (Figure 5). In the
the disease.64 They further demonstrated that in the damaged tissue, cicatricial or atrophic type, the clinical appearance involves lesions
the presence of hyphae and especially of muriform cells, but not of with an annular, serpiginous, or irregular configuration and centri-
conidia, correlates with the intense production of proinflammatory
cytokines in vivo. The analysis of high throughput RNA sequencing
showed strong regulation of genes related to fungal recognition, cell
migration, inflammation, apoptosis, and phagocytosis in macro-
phages exposed in vitro to muriform cells, but not to conidia. They
also demonstrated that only the muriform cells needed recognition
of FcγR and dectin-1 for in vitro internalization and that this is the
principal fungal form responsible for the intense inflammatory pat-
tern observed in CBM, thereby elucidating the chronic inflammato-
ry reaction seen in the majority of patients.64

CLINICAL MANIFESTATIONS
CBM manifests clinically as oligosymptomatic or asympto-
Figure 1: Types of CBM lesions according to Car-
matic lesions, which would explain why patients only tend to seek
rión (1950). Initial CBM lesion
medical care after months or even years of living with the disease.

Chart 1: Clinical classification of chromoblastomycosis types

according to Carrión (1950)
Nodular Fibrotic, erythematous-violaceous no-
dules, with smooth or hyperkeratotic
surface
Verrucous or warty Cauliflower-like, dry, hyperkeratotic le-
sions with black dots
Plaque (infiltrative Erythematous or violaceous plaques, in-
or erythematous) filtrated, circumscribed, irregular, sharp
and elevated edges, with black dots
Tumoral Isolated or coalescent lobulated lesions,
smooth or vegetative-like surface
Cicatricial or atrophic Annular, serpiginous, or irregular le-
sions with centrifugal growth and cen-
tral atrophic areas
Figure 2: Types of CBM lesions according to Carrión (1950). Nodular

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498 Brito AC, Bittencourt MJS

Figure 3: Types of CBM lesions according to Carrión (1950). Verrucous Figure 5: Types of CBM lesions according to Carrión (1950). Tumoral

Figure 4:
Types of
CBM lesions Figure 6: Types of
according CBM lesions accor-
to Carrión ding to Carrión (1950).
(1950). Plaque Cicatricial

fugal growth with atrophic central areas, in some cases occupying gions.27 The clinical manifestations of CBM display different degrees
large skin areas (Figure 6). of severity, as follows: 81
The great majority of CBM lesions are located on the lower Mild form: single lesion, plaque or nodular type, less than 5
limbs, especially in agricultural workers. Reports in the literature of cm in diameter (Figure 7A).
different clinical features and other sites include: localized annular Moderate form: single or multiple lesions, plaque, nodular,
form, diffuse cutaneous form, on the scapular region, two cases on or verrucous (verruciform). When multiple, presence of one or var-
the axillae, on the abdomen, on the cornea, on the conjunctiva simu- ious types of lesions located on one or two adjacent skin areas, less
lating melanoma, on the auricular region, and as a phagedenic ulcer than 15cm in diameter (Figure 7B).
on the face.43,66-76 Severe form: any type of single or multiple lesion, adjacent
Oral CBM was reported by Fatemi et al.77 Cases of extracu- or otherwise, covering extensive areas of the skin. When multiple,
taneous CBM are rare, but hematogenous, lymphatic, or contigu- combined presence of one or several types of lesions (Figure 7C).
ous dissemination of the fungus has been known to metastasize to Patients report pruritis of variable intensity in the lesions,
lymph nodes and lungs and produce osteolytic lesions underlying and pain in the presence of secondary infection. The following com-
the skin lesion.78-80 There are reports of fatal cases of brain abscesses plications occur in CBM: bacterial infection, elephantiasis, and car-
caused by F. monophora and F. pugnacius.22 cinomatous degeneration.82-90
Although most CBM patients are adults, cases of the myco-
sis have been reported in children and adolescents in endemic re-

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Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment update 499

A B C

Figure 7: CBM lesions according to severity criteria. A - mild; B - moderate; C - severe

DIFFERENTIAL DIAGNOSIS
The polymorphism of CBM lesions makes differential di- plete the diagnostic workup, and PCR tests have been developed
agnosis mandatory with pathological processes of different etiol- to identify Fonsecaea species and C. carrionii.21,26,92 In light of the im-
ogies, including: phaeohyphomycosis, paracoccidioidomycosis, mune response in CBM patients, Oberto-Perdigon et al. used ELISA
sporotrichosis, lobomycosis (lacaziosis), coccidioidomycosis, North in 114 sera to assess the humoral response before, during, and after
American blastomycosis, leishmaniasis, mycetoma, leprosy, cutane- treatment employing a somatic antigen (AgSPP) of C. carrionii.93 The
ous tuberculosis, non-TB mycobacterial infections, protothecosis, authors concluded that the method is valuable for diagnosis and as-
rhinosporidiosis, botryomycosis, tertiary syphilis, ecthyma, sar- sessment of therapeutic efficacy. However, PCR and ELISA are still
coidosis, psoriasis, halogenoderma, and neoplasms, including squa- not available in many endemic areas.
mous cell carcinoma, keratoacanthoma, and sarcoma (Figure 8). Histopathologically, CBM is characterized by an epidermis
with hyperparakeratosis, pseudoepitheliomatous hyperplasia, in-
LABORATORY DIAGNOSIS tracorneal microabscesses, and transdermal elimination of fungi,
Direct microscopy using potassium hydroxide (KOH) 10- the latter either inside or outside the microabscesses (Figure 11A and
20% or KOH/DMSO reveals muriform (sclerotic) bodies, pathog- 11B). The dermis presents dense granulomatous inflammation with
nomonic of CBM regardless of the causative species (Figure 9A). different degrees of fibrosis, consisting of mononuclear cells (histio-
Occasional dematiaceous hyphae may be associated with the mu- cytes, lymphocytes, and plasma cells), epithelioid cells, giant cells
riform bodies in the material (Figure 9B). The specimens with the (Langhans and foreign body types), and polymorphonuclear cells.
highest likelihood of a positive result are those from lesions with the Fungal cells with their characteristic micromorphology – round,
so-called “black dots” that are visible on the lesion’s surface, repre- dark-brown, thick-walled, 4-12 microns in diameter and with multi-
senting transdermal elimination of the fungus. Miranda et al. (2005) planar reproduction, called muriform (sclerotic) bodies – are found
used vinyl adhesive tape for the diagnosis of some deep mycoses, in intraepidermal microabscesses in multinucleated Langhans and/
including CBM.91 or foreign body-type cells, in suppurative or tuberculoid granulo-
Fungal culture in Sabouraud agar is used to isolate and mas, easily identified by hematoxylin-eosin staining (Figure 11C).
identify species, but the causative agents usually present very simi- Dimorphism may be observed, and it is possible to identify
lar macromorphological characteristics. F. pedrosoi produces velvety, hyphae and muriform bodies in material from skin lesions.94 Pires et
dark-brown, olive-green, or black colonies (Figures 10A and 10B). al., in a study of 65 patients that underwent histopathological exam-
Phialophora verrucosa produces slow-growing, velvety, moss-green, ination with HE staining, found two main types of granulomatous
brown, or black colonies. C. carrionii displays colonies very similar tissue reaction: suppurative granuloma with abundant fungal cells,
to those of F. pedrosoi (Figures 10C and 10D). R. aquaspersa colonies mostly from verrucous lesions, and tuberculoid granuloma, with
are velvety and moss-green to black. few parasites, from plaque and atrophic lesions.95
Microculture yields three types of fruiting or sporulation: There is an interesting report of detection of CBM agents
Cladosporium type – acrogenous catenulate sporulation, elliptical using Ziehl-Neelsen and Wade-Fite staining, a useful approach in
spores in chains; Phialophora type – conidiophore (phialide), flow- cases that are difficult with HE staining.96 Our study used Fite-Fara-
er vase-shaped with spores around the phialide; Rhinocladiella type co staining and showed the dimorphism of the fungus – presence
– conidiophores formed along the hyphae and oval spores on the of muriform bodies associated with dematiaceous septated hyphae
upper extremity (acrotheca) and along the conidiophore. (Figure 11D). Saxena et al. (2015) detected abundant fungi under
No intradermal tests for the disease have been standard- direct microscopy following intralesional infiltration of corticoste-
ized. Molecular biology techniques are currently essential to com- roids in a CBM lesion.97

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500 Brito AC, Bittencourt MJS

A B C D

E F G

Figure 8: Differential diagnosis. A - nocardiosis; B - verrucous paracoccidioidomycosis; C - lupus vulgaris; D: squamous cell carcinoma;
E - verrucous leishmaniasis; F - verrucous sporotrichosis; G - Jorge Lobo’s disease

Figure 9: Direct mycologic examination.

A - muriform bodies; B - Muriform bo-
A B
dies and dematiaceous hyphae

TREATMENT
CBM is difficult to treat and associated with low cure rates wide margins, and antifungal agents are often used before surgery
and high relapse rates, especially in chronic and extensive cases. to downsize the lesion and later to avoid risk of relapse. Electrodis-
Treatment choice and results depend on the etiological agent, size section and curettage are not recommended, since they can result in
and extent of the lesions, topography, and presence of complications. involvement of the lymphatic chain.98
Clinical cure can be defined as complete resolution of all the Cryotherapy or cryosurgery with liquid nitrogen and ther-
lesions, leaving scars. Mycological cure is proven by the absence of motherapy (local heat to produce controlled temperatures of 42-
fungi on direct mycological examination and negative culture. His- 45°C, which inhibit fungal growth) show minimal risk of adverse
topathology of the healed lesion shows atrophic epidermis and ab- effects, and these treatment options are relatively inexpensive, but
sence of granulomatous infiltrate and abscesses, which are replaced are more appropriate for single, limited lesions.99,100 Cryosurgery is
by cicatricial fibrosis associated with chronic inflammatory infiltrate relatively easy in technical terms, but the freezing time and depth
and absence of fungi in serial slices. have still not been standardized. Thermotherapy has been used less,
Treatment consists of long periods of antifungal drugs, of- and the cases with the best published results have been in Japan.
ten combined with physical treatments like surgery, cryotherapy, The technique requires daily application of heat directly on the le-
and thermotherapy. Studies report highly variable clinical and my- sions for several hours, for 2-6 months.101,102
cological cure rates, ranging from 15% to 80%.98 CO2 laser appears to be an interesting alternative for treat-
Small and localized lesions can be removed surgically with ment of well-demarcated, localized CBM lesions. One advantage is

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Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment update 501

A B

Figure 10: A - F. pedrosoi colony; B - F. pe-

drosoi microculture; C - C. carrionii colony;
C D
D - C. carrionii microculture

the need for only a single treatment, which improves patient adher- day of posaconazole, with clinical success in five of the six patients.
ence. In addition, the cost of a single treatment is relatively low, with Posaconazole was well tolerated during long-term administration.122
the advantage of no systemic toxicity.103 Combination treatment us- Oral voriconazole was tested in some cases of treatment in
ing CO2 laser and topical thermotherapy was used successfully in resistant forms of CBM.106,120,121 Good clinical results were achieved
CBM by Hira et al.104 with this drug, but adverse effects like visual disturbances and pho-
There was a recent promising description of photodynamic tosensitive skin reactions were observed.121
therapy in CBM.105,106 Hu et al. used oral terbinafine in combination Among the other antifungals, ketoconazole is not recom-
with photodynamic therapy with 5-aminolevulinic acid in a case of mended for prolonged treatment, because high doses are associated
CBM, with apparent clinical improvement in less than a year and no with toxicity. Fluconazole is also contraindicated, since in vitro stud-
recurrence. 107 Mohs micrographic surgery has been used to treat a ies have shown its limited activity against dematiaceous fungi.115
variety of skin neoplasms with excellent results. The technique was Fluorocytosine (converted into 5-fluorouracil in fungal
used successfully to treat a localized cutaneous CMB lesion, with no cells) shows some degree of efficacy but is associated with high risk
recurrence of the lesion after a year of follow-up.108 of development of resistance, besides being hepatotoxic and myelo-
The antifungals that have shown the greatest efficacy are toxic.123 With the emergence of more recent antifungals, the drug is
itraconazole (200-400mg/day) and terbinafine (500-1000mg/day) now rarely used except in selected resistant cases.
for at least 6-12 months, preferably at higher doses if tolerated.109-113 Amphotericin B is ineffective as monotherapy, and even in
Both drugs showed high in vitro activity against the causative agents combination with other antifungals the results are generally poor,
of CBM.114,115 Pulse therapy with itraconazole was reported (400mg/ but in vivo studies of a combination of amphotericin B and fluorocy-
day for 7 days/month) and proved more economical and effective tosine have shown efficacy, indicating synergistic activity between
and associated with better treatment adherence.116,117 In addition, the the two.124
combination of an azole (itraconazole) and an allylamine (terbina- The combination of itraconazole and fluorocytosine has
fine) with different targets and synergistic effect has been used.118 only been evaluated in a small number of patients but has prov-
Second-generation triazoles (voriconazole, ravuconazole, en very effective even in severe forms of subcutaneous mycoses.125
posaconazole, and isavocunazole) present in vitro activity against The pharmacological data showed an additive effect against fungi,
dematiaceous fungi and are promising drugs for treatment of deep where fluorocytosine causes suppression of the yeast’s DNA syn-
dermatomycoses, but the experience is limited by the prohibitively thesis and itraconazole acts on the cell membrane, inhibiting the
high costs in their endemic configuration.106,119-122 synthesis of ergosterol.126 Despite an insufficient number of cases for
Negroni et al.122 assessed six CBM patients that were resis- a detailed comparison, combination therapy with these two drugs
tant to conventional antifungal therapies and administered 800mg/ can be an option in severe cases of CBM.126

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502 Brito AC, Bittencourt MJS

A B

Figure 11: Histological features. A - Pseu-

doepitheliomatous hyperplasia, hyperpa-
rakeratosis, and dermis with edema and
granulomatous inflammatory infiltrate
(Hematoxylin & eosin, x40); B - Muri-
form cells in the stratum corneum with
transdermal elimination(Hematoxylin &
eosin, x400); C - Suppurated granuloma
with muriform bodies inside giant cells
(Hematoxylin & eosin, x400); D - Muri-
C form cells and septated hyphae in abscess
D
(Fite-Faraco staining) x100

The combination of antifungal drugs with immunoadjuvant Imiquimod is a synthetic compound with potent antitumor-
compounds such as glucan and imiquimod have been investigated al, immunomodulatory, and antiviral action, which stimulates both
in recent years.5 Glucan, an injectable formulation of β1→3 polygly- the innate and acquired immune pathways.131 Souza et al. discov-
coside obtained from Saccharomyces cerevisiae, is considered a modi- ered an underlying defect in the innate recognition of CBM agents
fier of the biological response due to its immunomodulatory poten- by toll-like receptors (TLRs), which can be restored by exogenous
tial, since it can be recognized by specific cell receptors and has the administration of a TLR agonist, including imiquimod. 132 Imiqui-
ability to enhance the host immune response, with the activation mod was used in a study with topical application 4 to 5 times a
of macrophages, endothelial and dendritic cells, B and T-cells, and week in association with oral itraconazole, with a good clinical re-
polymorphonuclear lymphocytes, with the resulting induction of sponse.133
expression of various cytokines like TNF-α, IL-6, IL-8, and IL-12.127
This treatment has been used successfully in some cases of leish- CONCLUSIONS
maniasis and paraccocidiodomycosis.128 In CBM, glucan was used CBM is an important deep cutaneous mycosis which still
in weekly subcutaneous infections combined with itraconazole, causes major morbidity in affected patients. It is extremely diffi-
with a good clinical response.129,130 Azevedo et al. (2008) showed cult to treat, especially in the more severe clinical forms. Treatment
that after treatment with glucan, there was a significant increase in generally consists of long periods of treatment with antifungals, of-
lymphoproliferation of the patient’s cells in the presence of F. pe- ten associated with physical treatments and immunotherapy. New
drosoi antigens, with altered cytokine pattern, showing a decrease studies are being published that help elucidate the immunopatho-
in the production of IL-10 and a significant increase in IFN-γ and genesis of this mycosis, aimed at developing new therapies capable
TNF-α.129 of modulating the host immune response. q

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Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment update 503

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AUTHORS CONTRIBUTION

Arival Cardoso de Brito 0000-0002-7133-5321

Approval of the final version of the manuscript; Conception and planning if the study;
Elaboration and writing of the manuscript; Obtaining, analyzing and interpreting the
data; Effective participation in research orientation; Intellectual participation in pro-
paedeutic and/or therapeutic conduct of cases studied; Critical review of the literature;
Critical review of the manuscript

Malaya de Jesus Sembilan Bittencourt 0000-0002-7297-0749

Conception and planning of the study; Elaboration and writing of the manuscript; Ob-
taining, analyzing and interpreting the data; Effective participation in research orien-
tation; Intellectual participation in propaedeutic and/or therapeutic conduct of cases
studied; Critical review of the literature

How to cite this article: Brito AC, Bittencourt MJS. Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment
update. An Bras Dermatol. 2018;93(4):495-506.

An Bras Dermatol. 2018;93(4):495-506.

506 Brito AC, Bittencourt MJS

QUESTÕES s

1. The following are causative species of CBM, except: 7. As for the immunology of chromobastomycosis, mark
a) Fonsecaea pedrosoi the CORRECT answer:
b) Cladophialophora carrionii a) Verrucous lesions show a predominance of IL4 and
c) Rhinocladiella aquaspersa IL10
d) Penicillium marneffei b) Humoral immune response predominates
c) Th2 profile predominates in atrophic lesions
2. Melanin (dihydroxy naphthalene-melanin) in the wall d) Low expression of IL-17 in the lesions
of etiological agents of CBM is considered:
a) A factor for resistance to antifungal agents 8. The black dots in CMB lesions represent:
b) A factor for virulence pathogenicity a) Thrombosed vessels on the lesion’s surface
c) Only defines the color b) Hematic crusts
d) A reproductive factor c) Transdermal elimination of the fungus
d) Melanocyte proliferation
3. The following are considered clinical forms of CMB,
except: 9. As for classification of CBM lesions according to Que-
a) nodular iroz-Telles, the mild form is characterized by:
b) verrucous a) Single lesion, plaque or nodular type, less than 5cm in
c) macular diameter
d) tumoral b) Single lesion, plaque or nodular type, less than 10cm
in diameter.
4. As for antifungals used in the treatment of chromomy- c) Single verrucous lesion less than 5cm in diameter.
cosis is CORRECT to afirm: d) Multiple lesions, plaque or nodular type, less than
a) Itraconazole and terbinafine show low in vitro activity 5cm in diameter.
against the etiological agents of CBM.
b) Second-generation triazoles (voriconazole, ravuco- 10. The etiological agents of CBM belong to the family:
nazole, posaconazole) do not display in vitro activity a) Ajellomycetaceae
against dematiaceous fungi. b) Botryobasidiacea
c) Ketoconazole is still recommended as an option for c) Herpotrichiellaceae
prolonged treatment. d) Hydnaceae
d) Fluconazole is not recommended, since in vitro studies
showed little activity against dematiaceous fungi.

5. Concerning the use of amphotericin for the treatment

of CBM, mark the CORRECT answer: Answer key
a) Quite effective as monotherapy Tuberous sclerosis complex: review based on new
b) Safe drug for severe forms of the disease diagnostic criteria. An Bras Dermatol. 2018;93(3):
c) The combination with fluorocytosine has shown effi- 323-31.
cacy in in vitro studies
d) The drug of choice for localized lesions 1. A 3. B 5. D 7. D 9. C
2. D 4. D 6. A 8. B 10. C
6. Cladosporium type fruiting is characterized by:
a) Flower vase-shaped conidiophore (phialide) with
spores around the phialide
b) Conidiophores formed along the hyphae and oval
spores on the upper extremity (acrotheca) Papers
c) Acrogenous catenulate sporulation, elliptical spores in Information for all members: The EMC-D questionnaire
chains. is now available at the homepage of the Brazilian Annals
d) Brush-shaped conidiophore of Dermatology: www.anaisdedermatologia.org.br. The
deadline for completing the questionnaire is 30 days from
the date of online publication.

An Bras Dermatol. 2018;93(4):495-506.