Chromoblastomycosis caused by Phialophora macrospora

Dear Editors, Chromoblastomycosis (CBM) is one of the more prevalent sporadic subcutaneous fungal infections, primarily affecting individuals residing in tropical and subtropical regions worldwide. Although the term “chromoblastomycosis” was first introduced in 1922, research on the disease began as early as 1911 in Brazil. Chromoblastomycosis lesions are frequently misdiagnosed as various other infectious or noninfectious diseases.1 Fungal species known to cause CBM include genera such as Fonsecaea, Cladophialophora, Exophiala, Phialophora, and Rhinocladiella.2-4 Awareness of identification methods is crucial, as different species of Fonsecaea may result in distinct prognoses.5 The research from a single medical center found that ten patients (33.3 %) had diabetes, which was the most common comorbidity among the 30 patients enrolled. None of the patients received steroid or immunosuppressive therapy at the time of diagnosis.2 A 56-year-old male farmer presented with erythematous plaques on his left forearm persisting for 20 years. The lesion initially manifested as a papule and gradually extended to the upper arm, forming an erythematous plaque. There were no prior episodes, additional cutaneous lesions, systemic symptoms, or history of insect or animal bites. Dermatological examination revealed erythema and plaques on the left palm, dorsum of the hand, and forearm, accompanied by thick adherent keratotic scales and dark-brown crust-like deposits (Figure 1a,b). Results of histopathological examination demonstrated infectious granuloma with round spores identified within multinucleated giant cells (Figure 1c). Dark brown filamentous colonies were observed on Sabouraud dextrose agar after 14 days of incubation at 26 °C (Figure 1d). Fungal genomic DNA was extracted and subjected to molecular identification via sequencing to confirm the genotype of the causative agent. In slide culture, regularly septate, brown hyphae were observed, accompanied by subglobose conidia that formed cohesive clusters at the apices of vase-shaped phialides with prominent flaring collarettes (Figure 1e). DNA sequencing confirmed the strain as Phialophora macrospora. The diagnosis of chromoblastomycosis was ultimately established. The patient received combination therapy consisting of acitretin 20 mg and itraconazole 200 mg once daily for two months, followed by itraconazole 200 mg once daily for an additional six months. Significant improvement in skin lesions was observed within one month, with complete resolution achieved in eight months. During the period of combined therapy, hepatic and renal functions were closely monitored and remained within normal limits throughout the treatment. Chromoblastomycosis (CBM) is a chronic cutaneous and subcutaneous infectious disease that primarily affects immunocompetent individuals engaged in agricultural or gardening activities, typically due to exposure to contaminated soil or vegetation.6 It primarily affects the lower limbs of male rural workers.7 The infection is typically initiated by transcutaneous traumatic inoculation of various melanized fungal species into the human body.3 The clinical presentation of CBM is variable, typically manifesting as chronic warty, nodular, or cauliflower-like cutaneous lesions and eruptions.4 Cicatricial and tumorous types are less frequently observed.1 Lesions typically affect the extremities.2, 3 Diagnosis depends on direct microscopy, histopathology, culture, and molecular identification when necessary. The rarity of P. macrospora as an etiological agent underscores the importance of molecular characterization. First described in 1915, the fungal genus Phialophora has only recently been subjected to molecular characterization to define and delineate species boundaries in a contemporary context.4, 8 Notably, P. macrospora has rarely been reported as an independent etiological agent; in one study from Mexico, molecular analysis confirmed two such cases among a cohort of chromoblastomycosis patients.4 Management of chromoblastomycosis remains a major challenge, largely attributable to delayed diagnosis and the refractory course of the disease. Treatment often involves systemic antifungal therapy, surgical excision for early lesions, or a combination of both approaches. Itraconazole followed by terbinafine is considered the preferred sequence of oral antifungal agents for managing patients with chromoblastomycosis.7 The current recommendation for treating CBM also includes combination with conventional surgery or cryosurgery.9 A similar case at our institution was successfully treated with a combination of itraconazole and acitretin.10 In contrast, the previously reported case was caused by Fonsecaea monophora in a patient with concomitant psoriasis, which required simultaneous management of both the psoriatic condition and the fungal infection. Therefore, we adopted combination therapy with itraconazole and acitretin, resulting in a rapid and substantial improvement in both the fungal verrucous lesions and the psoriasis-like plaques within only 16 days of treatment. The rationale for this combination therapy in our patient, who did not have psoriasis, was based on established pharmacological principles. The primary goal was to leverage the potent keratoregulatory, anti-proliferative, and anti-inflammatory properties of acitretin11 as an adjuvant to itraconazole. This approach, targeting the prominent hyperkeratotic component of the CBM lesions, is supported by the reported efficacy of acitretin in other recalcitrant hyperkeratotic or verrucous dermatoses, such as lamellar ichthyosis, recalcitrant warts, and epidermodysplasia verruciformis.12-14 Although the lesion in this patient had persisted for two decades, remarkable clinical improvement was observed within the initial two months of treatment. The patient subsequently achieved complete resolution following a regimen of itraconazole 200 mg once daily for an additional six months, with the overall therapeutic outcome being highly satisfactory. Furthermore, the potential for adverse effects and drug interactions with this combination must be considered. Acitretin is associated with well-documented risks; its known contraindications include teratogenicity, impaired liver or kidney function, and chronic hyperlipidemia. Although direct drug interactions between itraconazole and acitretin have not been confirmed, related retinoids such as isotretinoin have shown decreased metabolism when co-administered with itraconazole, as reported in DrugBank.15 No hepatic or renal impairment was observed in our patient during the combination therapy. Taken together, these observations raise the possibility that the clinical improvement observed in our patient may have been facilitated by a synergistic effect between the two drugs, although its mechanism remains unknown. We acknowledge that the precise contribution of acitretin to the treatment success in our case cannot be quantitatively determined. Although the observed clinical improvement suggests a possible synergistic effect, the evidence remains anecdotal. Given these uncertainties in both efficacy and safety, further clinical experience and comparative studies are needed to clarify the potential role of acitretin in this setting. Therefore, at present, no recommendation can be made for the routine use of this combination therapy. Shandong Province Taishan Scholar Project (tspd20230608, tsqn202211345), Shandong Provincial Natural Science Foundation (ZR2024MH192), Shandong Provincial Medical and Health Development Project (202320000591). None.