Chromoblastomycosis: A Single Centre Clinical Laboratory Experience of Seven Years (2016-2022) and Literature Review From Pakistan.

BACKGROUND: Chromoblastomycosis (CBM) is a chronic infection of skin and subcutaneous tissue. CBM cases have been reported in local literature from Pakistan with heterogenous demographic, diagnostic and therapeutic information. The objective of this study is to share the experience of CBM from a large tertiary care hospital laboratory in Pakistan. METHOD: This was a retrospective observational study. Histopathology and microbiology data of suspected CBM between 2016 and 2022 was retrieved. Patients' demographics, site of involvement, histopathological findings and positive microbiology cultures were assessed. Literature search on Google Scholar, PubMed and PakMediNet was done between 1990 and 2023 with multiple terms. RESULT: A total of 16 CBM cases were identified; 14 were histopathology positive and two were both histopathology and culture positive. The median age was 21 years, and 11 patients were male. The predominant site was lower extremities followed by the face. Severe acanthosis, hyperkeratosis and granuloma with sclerotic bodies were observed in all histopathology slides. Alternaria spp. and Phialophora spp. were isolated from two culture-positive cases. A total of nine cases of CBM were reported from Pakistan in PubMed non-indexed journal. CONCLUSION: CBM is not a commonly thought of disease when evaluating skin lesions in Pakistan. A high index of suspicion when assessing patients who may have a history of trauma, exposure to soil and suggestive lesions is reasonable. An integrated approach between clinicians, histopathologist and microbiologist is required to do early identification and therapeutic interventions.

Inflammasome and Inflammatory Programmed Cell Death in Chromoblastomycosis.

Chromoblastomycosis (CBM) is a chronic, progressive fungal disease of the skin and subcutaneous tissue caused by a group of dematiaceous fungi. Verrucous lesions present parasite-rich granulomas and predominance of a Th2 patterns of cytokines. The inflammasome constitutes a macromolecular protein complex that play a role in the activation of caspase 1 that cleaves pro-IL1ß and pro-IL18, essential mediators of inflammation, and also activates pyroptosis. We intended to explore the presence and a possible role of inflammasome elements in cutaneous human lesions in CBM, considering the expression of IL1ß, IL18, caspase 1, NLRP1, and also RIPK3, a key downstream component of necroptosis signaling. 35 skin biopsies of cutaneous lesions of verrucous form of CBM and 10 biopsies from normal skin were selected. The diagnosis was based on histological and clinical analysis. An immunohistochemical protocol was performed. The histopathological analysis evidenced epidermis with hyperkeratosis, irregular acanthosis, and micro abscesses. The dermis presented suppurative granulomas and inflammatory infiltrate composed by giant cells, macrophages, epithelioid cells, lymphocytes, and some eosinophils. Positive cells were distributed in the inflammatory infiltrate, with an increased number of cells expressing caspase 1, IL1ß and IL18. Cells expressing RIPK3 and NLRP1 were less frequent. The intense presence of caspase 1, IL1ß and IL18, allied to NLRP1 expression, suggest that inflammasome and pyroptosis could play a role in the immune response against fungal agents of CBM. Our results, allied to data from literature, could suggest that inflammasome-mediated response and pyroptosis could be a target to be explored to decrease CBM lesions.

Retinoid combined with photodynamic therapy against hyperkeratotic chromoblastomycosis: A case report and literature review.

Chromoblastomycosis (CBM) is a chronic granulomatous fungal infection caused by melanised or brown-pigmented fungi. It can lead to chronic persistent infections and may cause incapacity for labour in some severe clinical forms. The optimal therapy for CBM is still uncertain. Here, we reported the case of a 66-year-old male who has had red plaque and recurrent keratinised protrusions on his right forearm for 20 years. He was treated orally with terbinafine, itraconazole and isotretinoin. He also received carbon dioxide(CO2 ) laser to eradicate the keratinised protrusions and promote the penetration of photosensitiser. After the CO2 laser, 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) was adopted immediately to inhibiting the growth of fungi in subcutaneous tissue. The patient received an important improvement with a plaque and crust reduction after 4 months. For such recalcitrant case of chromoblastomycosis, the use of retinoid, CO2 laser combined with ALA-PDT may be a new adjuvant therapy. We further reviewed the cases of chromoblastomycosis treated with laser, photodynamic therapy or retinoic acid.

Case Report: A Case of Chromoblastomycosis Caused by Fonsecaea pedrosoi in Vietnam.

BACKGROUND: Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues caused by different melanized fungi. The disease occurs worldwide, particularly in tropical and subtropical regions but not reported in Vietnam. A 47-year-old women was admitted to hospital 103, Hanoi, Vietnam, with a 10-year lasting lesion on backside of her right shank. Diagnosis of chromoblastomycosis was made after discovery of a muriform cell in histopathological examination. A black, slow-growth fungus was isolated and identified as Fonsecaea pedrosoi after molecular analysis. After 1-month treatment with itraconazole, the lesion has significant improvement. CONCLUSION: This is the first case of chromoblastomycosis caused by Fonsecaea pedrosoi reported in Vietnam.

Chromoblastomycosis Caused by Fonsecaea nubica: First Report in Northern China and Literature Review.

Chromoblastomycosis is found worldwide with higher incidence in tropical and subtropical regions. Fonsecaea spp. is one of the major causative agents of this disease. First case of chromoblastomycosis due to Fonsecaea nubica in Northern China is reported in a 75-year-old Chinese male. We firstly summarized molecular identification methods of Fonsecaea spp. and all the strains of F. nubica reported in the literature. Sequencing of internal transcribed spacer alone and/or combined with actin (ACT1), partial cell division cycle (CDC42) and partial beta-tubulin (BT2) were most commonly used to identify species, while lactase (Lac), homogentisate (HmgA) and polyketide synthase (PKS1) were also used in some cases. Most strains were isolated from South America and Eastern China. Five clinical cases of chromoblastomycosis due to F. nubica from Asia and Europe were also reviewed. All the five patients were male, over 30 years old, and their lesions occurred after trauma.

Successful treatment of chromoblastomycosis of 10-year duration due to Fonsecaea nubica.

We report a case of chromoblastomycosis due to the presence of large plaque and verrucous hyperplasia lesions on the left upper limb, with elbow abnormal activities, in a 56-year-old male. The diagnosis of chromoblastomycosis was based on gross and microscopic morphologies, histopathological examination and clinical manifestation. Molecular tools were applied to identifying the causative agent Fonsecaea nubica, which is rarely reported to be associated with chromoblastomycosis. The patient was initially treated orally with terbinafine (250 mg/day) and itraconazole (200 mg/day), subsequently patient received thermotherapy (45-50°C, 3 h/day) for 1 month. The patient was successfully cured. A literature review was performed to assess general features, treatment and outcome of chromoblastomycosis due to F.  nubica. All the 5 reviewed patients were male, over 30 years old and their lesions occurred after traumatic inoculation.

Study on the organization of cellular elements in the granulomatous lesion caused by chromoblastomycosis.

BACKGROUND: Chromoblastomycosis is a deep fungal infection characterized by a complex cellular granuloma. The aim of this study was to analyze the arrangement of cells responsible for the granuloma configuration of this disease by semiquantification of the cellular components of chromoblastomycosis skin biopsies. METHODS: The cells of cutaneous biopsies slides from 100 patients with untreated chromoblastomycosis were stained with hematoxylin-eosin and the granuloma cells were evaluated by microscopic examination of the elements of each granuloma and semiquantified the number of cells through its expressivity in crosses and the histopathological variables. Their presence were coded in degrees of intensity and classified in two categories: low expression and high expression. The cells that constituted the granulomas were separated into three groups: A, B and C. RESULTS: The chromoblastomycotic granuloma analyzed by this semiquantification of its cellular components showed that there was high expression of the elements setting up a mixed organized mycotic granuloma. It was observed that mononuclear phagocytic system (A), polymorphonuclear phagocytic system (B) and lymphoplasmocytic infiltrate (C) were located around the fungus. CONCLUSION: The results indicated that the granuloma present in the cutaneous lesion of chromoblastomycosis is a mixed organized mycotic granuloma with high expression of the cellular components.

Chromoblastomycosis of the leg.

CASE REPORT: We herein report a case of chromoblastomycosis presenting as a verrucous lesion over the leg. A 56-year-old male patient was a known case of carcinoma larynx and was treated for the same. At presentation to our hospital, the patient, in addition to the recurrent local disease, was suspected to have second primary in the form of verrucous carcinoma of the leg. Histopathological examination of the skin biopsy revealed the presence of characteristic pigmented sclerotic bodies with pseudoepitheliomatous hyperplasia of the overlying epithelium. The case was reported as chromoblastomycosis and the patient responded well to anti-fungal chemotherapy in the form of itraconazole.

Fonsecaea pedrosoi-induced Th17-cell differentiation in mice is fostered by Dectin-2 and suppressed by Mincle recognition.

Chromoblastomycosis is a chronic skin infection caused by the pigmented saprophytic mould Fonsecaea pedrosoi. Chronicity of infection can be broken by a coordinated innate recognition of the spores by pattern recognition receptors. While Mincle signaling via the Syk/Card9 pathway is required for fungal recognition by host cells, it is not sufficient for host control. Exogenously applied TLR agonists are necessary to promote the induction of proinflammatory cytokines and clearance of infection in vivo. Here, we investigated whether costimulation by TLR agonists fosters the development of adaptive immune responses, by examining the development of fungus-specific T cells. Subcutaneous infection of mice with F. pedrosoi spores induced the activation, expansion, and differentiation of Ag-specific CD4(+) T cells but TLR costimulation did not further augment these T-cell responses. The Dectin-2/FcRγ/Card9 signaling pathway promoted the differentiation of fungus-specific CD4(+) T cells into Th17 cells, whereas Mincle inhibited the development of this T-helper subset in infected mice. These results indicate differential roles for Dectin-2 and Mincle in the generation of adaptive immune responses to F. pedrosoi infection.

Wide Morphologic Variability of Chromoblastomycosis in the Western Hemisphere.

Chromomycosis is an uncommon fungal disease seen in tropical and subtropical regions of the world. The disorder is most likely the result of traumatic percutaneous inoculation of one of several etiologic dematiaceous fungi. Causative organisms have been associated with dead wood, soil, and plants. Chromomycosis may present clinically in a wide variety of manners. We illustrate the characteristic morphologic appearances of mycosis as it was encountered in both Panama and Texas, including verrucous papules and nodules, scaly plaques, exophytic or ulcerative tumor-like masses, and cicatricial plaques of both small and large dimension. As is typical of this disease, all lesions in this series were located on the extremities, and all patients had frequent and intimate exposure to vegetation in hot, humid environments. Chromomycosis characteristically runs an indolent course and is rarely fatal. The patients described herein had experienced cutaneous lesions for many months to several decades prior to diagnosis. This mycosis is often difficult to treat. Successful therapy may involve one or more oral antifungal drugs (such as itraconazole and terbinafine) and/or use of physically ablative modalities (such as laser, photodynamic therapy, and cryosurgery).

Squamous cell carcinoma derived from chronic chromoblastomycosis in Brazil.

BACKGROUND: Chromoblastomycosis (CBM) is a chronic fungal infection caused mainly by the melanized fungi Fonsecaea species. The chronic lesions may be predisposed to develop into cancer, the most serious complication of the disease. METHODS: In this report, 7 cases of squamous cell carcinoma (SCC) resulting from chronic CBM in patients from Maranhão in the Brazilian Amazon are described. RESULTS: The 7 patients presented with SCC that resulted from chronic CBM, caused by Fonsecaea species >10 years' duration. The malignant lesions occurred independent of the antifungal therapy and all patients underwent curative amputation, except for 1 patient who developed metastases in the inguinal and intra-abdominal lymph nodes and thigh muscles. A majority of previous reports have focused on the malignant transformation of CBM described in only 1 patient each. This is a first report describing a group of patients from a single Brazilian state. CONCLUSIONS: Here, we provide new epidemiologic data on malignant CBM lesions, an endemic disease that is seemingly neglected worldwide. We reinforce the idea that typically chronic lesions may be predisposed to turn malignant.

Fonsecaea pugnacius, a Novel Agent of Disseminated Chromoblastomycosis.

We report a fatal case of a chromoblastomycosis-like infection caused by a novel species of Fonsecaea in a 52-year-old immunocompetent Caucasian male from an area of chromoblastomycosis endemicity in Brazil. The patient had a 30-year history of slowly evolving, verrucous lesions on the right upper arm which gradually affected the entire arm, the left hemifacial area, and the nose. Subsequent dissemination to the brain was observed, which led to death of the patient. The internal transcribed spacer (ITS) and partial large subunit (LSU), BT2, and CDC42 genes of the isolates recovered from skin and brain were sequenced, confirming the novelty of the species. The species is clinically unique in causing brain abscesses secondary to chromoblastomycosis lesions despite the apparent intact immunity of the patient. Histopathologic appearances were very different, showing muriform cells in skin and hyphae in brain.

Chromoblastomycosis due to Fonsecaea monophora in a man with nephritic syndrome.

Chromoblastomycosis is a chronic subcutaneous mycosis caused by dematiaceous fungi. Fonsecaea monophora, a new species segregated from F. pedrosoi, may be the most prevalent pathogen of chromoblastomycosis in southern China. Herein, we report a rare case of chromoblastomycosis in a man with nephritic syndrome. He presented with an asymptomatic red plaque on the back of his left wrist that had appeared and enlarged over a period of 1.5 years, without any prior trauma. He was initially diagnosed with sporotrichosis. However, he did not respond to a 6-month course of potassium iodide treatment. The lesion slowly enlarged and became verrucous instead. Concurrently, a similar maculopapule appeared on his left forearm. Histopathological examination of a biopsy specimen indicated the presence of sclerotic bodies in the dermis. The fungus was identified as Fonsecaea spp. based on the results of a slide culture; in addition, the agent was confirmed to be F. monophora by using molecular methods. The patient demonstrated marked improvement after receiving appropriate antifungal therapy for 3 months. To our knowledge, this is the first case of chromoblastomycosis caused by F. monophora in an immunosuppressed patient. The identification of the agent by molecular techniques is important for epidemiological purposes. Thus, we believe that combination therapy with itraconazole and terbinafine would be a suitable option for infections caused by F. monophora.

Cutaneous Chromoblastomycosis Caused by Veronaea botryosa in a Patient with Pemphigus Vulgaris and Review of Published Reports.

Chromoblastomycosis and phaeohyphomycosis represent two poles of a disease spectrum caused by melanized fungi. Veronaea botryosa belongs to a small genus of saprobic fungi that occasionally cause human infections. To date, 11 cases of V. botryosa-induced cutaneous phaeohyphomycosis have been actually reported since 1990 after exclusion of 2 duplicated cases. We report the first case to our knowledge of cutaneous chromoblastomycosis caused by V. botryosa in a patient with pemphigus vulgaris. A 61-year-old man with 5-year history of pemphigus vulgaris and long-term treatment of corticosteroids and immunosuppressive agents developed multiple nodules on the dorsum of right wrist and hand after wrist trauma. Skin biopsy showed numerous brown muriform cells and a few septate hyphae in the tissue. Veronaea botryosa was isolated from the biopsy samples and then identified based on morphologic observation and DNA sequencing. The patient underwent immediate withdrawal of cyclophosphamide and gradual decrease in prednisone. Skin lesions healed after 5-month itraconazole therapy with an interval of 1-month terbinafine and one cycle of liquid nitrogen cryotherapy. Our results demonstrate that V. botryosa could induce both chromoblastomycosis and phaeohyphomycosis. Combined use of itraconazole and cryotherapy may be preferable to treat this infection.

Chromoblastomycosis Caused by Cladophialophora bantiana in a Renal Transplant Recipient From Delhi, India.

A 45-year-old accountant residing in Delhi, India, presented to our dermatology clinic with a small asymptomatic plaque on the little finger of his left hand of 3 months' duration. The onset of the lesion was insidious and gradually progressed to 4 cm across at the time of his first visit. The patient had undergone renal transplantation twice (the first procedure 3 months prior and the second 18 months prior). Since then, he had been receiving cyclosporine A (400 mg daily) and prednisolone (40 mg) daily in immunosuppessive doses. The patient denied any kind of cutaneous injury prior to the onset of the lesion and any similar lesions in the past.

Association of IgG immunoglobulin and subclasses level with the severity of chromoblastomycosis due to Fonsecaea pedrosoi and therapeutic response to itraconazole.

Chromoblastomycosis (CBM) is a chronic, suppurative, granulomatous mycosis of the skin and subcutaneous tissues. The aim of this study was to evaluate the association between IgG antibody levels and the severity of CBM and therapeutic response of patients to itraconazole. A longitudinal study was conducted in patients with CBM due to Fonsecaea pedrosoi and in healthy subjects with chromomycin skin test (CST)+. The dosage of anti-F. pedrosoi IgG antibody performed in 47 healthy individuals with CST+ showed positivity in 97.5 %, with an average titer of 2,109 [standard deviation (SD) + 3,676)] and a mean optical density (OD) of 1.174 (SD + 0.456), showing positive correlation with the induration area of the CST (mm(2)). The level of antibodies in 55 patients with CBM expressed in OD and titration showed that, before treatment, patients with severe disease had higher levels of IgG, IgG1, IgG2, and IgG3 when compared with moderate or mild disease (p < 0.05). According to the time of treatment, the mean antibody titers of IgG, IgG1, and IgG2 were reduced after treatment (p < 0.05). In the assessment of therapeutic response, there was reduction of IgG3 and IgG titers in patients with rapid response (p < 0.05) and IgG2 on rapid and intermediate response (p < 0.05). There was clear evidence of what are the risk factors for exposure to F. pedrosoi in the daily lives of these subjects, with prospects of preventive measures for the target population. The immunological analysis shows that the antibody anti-F. pedrosoi did not exhibit a protective role against infection caused by this agent.

Plasmacytoid dendritic cells in cutaneous lesions of patients with chromoblastomycosis, lacaziosis, and paracoccidioidomycosis: a comparative analysis.

Plasmacytoid dendritic cells (pDCs) are characterized by expression of CD123 and BDCA-2 (Blood Dendritic Cell Antigen 2) (CD303) molecules, which are important in innate and adaptive immunity. Chromoblastomycosis (CBM), lacaziosis or Jorge Lobo's disease (JLD), and paracoccidioidomycosis (PCM), are noteworthy in Latin America due to the large number of reported cases. The severity of lesions is mainly determined by the host's immune status and in situ responses. The dendritic cells studied in these fungal diseases are of myeloid origin, such as Langerhans cells and dermal dendrocytes; to our knowledge, there are no data for pDCs. Forty-three biopsies from patients with CBM, 42 from those with JLD and 46 diagnosed with PCM, were evaluated by immunohistochemistry. Plasmacytoid cells immunostained with anti-CD123 and anti-CD303 were detected in 16 cases of CBM; in those stained with anti-CD123, 24 specimens were obtained from PCM. We did not detect the presence of pDCs in any specimen using either antibody in JLD. We believe that, albeit a secondary immune response in PCM and CBM, pDCs could act as a secondary source of important cytokines. The BDCA-2 (CD303) is a c-type lectin receptor involved in cell adhesion, capture, and processing of antigens. Through the expression of the c-lectin receptor, there could be an interaction with fungi, similar to other receptors of this type, namely, CD207 in PCM and CD205 and CD209 in other fungal infections. In JLD, the absence of expression of CD123 and CD303 seems to indicate that pDCs are not involved in the immune response.