Chromoblastomycosis is a chronic infection caused by dematiaceous (dark-colored) fungi which affect the skin and subcutaneous tissues, and is characterized by a wide variety of clinical and dermatological features including papillomatous, verrucous and vegetating lesions. Although it has been described world-wide, most cases originate in tropical and sub-tropical areas. In general, present treatments of the disease are unsatisfactory as one of the most common etiologic agents, Fonsecaea pedrosoi is difficult to manage from a therapeutic point of view. We report a case of extensive chromoblastomycosis of 22 years duration caused by F. pedrosoi and review the clinical course, diagnosis and management of this disease.
Chromoblastomycosis is a fungal infection of the skin and subcutaneous tissue caused most commonly by such dematiaceous fungi as Fonsecaea pedrosoi, Phialophora verrucosa, Rhinocladiella aquaspersa and Cladophialophora carrionii1–3. In addition, less frequently encountered etiologic agents that have been described include Exophiala jeanselmei, Exophiala spinifera, Exophiala dermatitidis4–6 and Cladophialophora bopii3, 6. Together with sporotrichosis and mycetoma, chromoblastomycosis is one of the most frequently encountered subcutaneous mycoses 1.
The disease usually affects rural male workers 1, mainly in tropical and humid areas of the world. In contrast, it has been most frequently described in xerophic and warm areas of Venezuela 7. Clinically, it appears as a chronic insidious infection—generally in lower limbs—presenting initially as nodules or papules which later become verrucous and confluent, leading to plaque formation. Dissemination and systemic chromoblastomycosis are rare 6. In general, treatment of this mycosis constitutes a therapeutic challenge for clinicians 4.
The patient was a 44-year-old male agriculture worker of Creole ethnic origin from the north western region of the coastal mountain range of Venezuela. The infection started as a solitary nodule on his right knee (without prior traumatic implantation) and over the next 22 years, multiple lesions formed at the site that expanded to confluent nodular groups with a tendency to form verrucous plaques with central clearance. In between the verrucous maculae were isles of uncompromised interlesional skin and atrophic areas. He had been unsuccessfully treated over the course of 15 years with mono and combined therapy which included ketoconazole and fluconazole.
When the patient was evaluated, he was found to have an extensive plaque mainly compromising the dorsal area of his right foot and extending to the upper third of the thigh. The lesions were as described above, as well as erythemathous crusted papules and plaques, hyperkeratosis in most areas with concomitant stabbing pain and pruritus, and joint anchilosis all of which severely limited the functionality of the limb (Fig. 1A, 1B).
Direct examination of the surface squamous-crusted lesions cleared with 20% potassium hydroxide (KOH) revealed the presence of pigmented fungal cells with thick walls (Fig. 2A). Biopsies taken from the periphery of the lesions showed slight laminar hyperkeratosis, as well as pseudocarcinomatous hyperplasia with microabscesses. At the dermal level there were granulomas with well epithelioid differentiation, Langhans-type cells with a lymphohistiocytic inflammatory infiltrate, and polymorphonuclear neutrophils with presence of muriform cells (Fig. 2C–F).
The tissue samples taken from the active border of the lesions were cut into thin slices and cultured in Sabouraud's dextrose agar. Dark green to brown colonies with a velvety aspect were found slowly developing at room temperature and at 37°C (Fig. 3). Microscopic examinations of slide cultures were conducted in order to preserve the structural organization of conidial development. Observation of the lactophenol cotton blue stained cover-slips from these cultures revealed a sporulation pattern characterized by long and ramified chains containing four to six conidia typical of F. pedrosoi (Fig. 2B).
The rest of the physical examination of the patient was uneventful. Complete blood count (CBC) and blood chemistry showed normal values. Human immunodeficiency virus (HIV), Human T-lymphotropic virus (HTLV), parvovirus, Epstein Barr virus (EBV) and Citomegalovirus (CMV) serological studies were all negative. The CD4/CD8 count appeared within normal limits. Cell-mediated response measured by an intradermal reaction was positive for candidine and tuberculine. A CT scan of the affected limb did not reveal any alterations other than the important fibroid component restricted to soft tissues.
Combined therapy with amphotericin B and itraconazole was implemented. Amphotericin B was initiated at 50 mg/day for five days which was then lowered to 25 mg/day, until reaching a cumulative 2,150 mg dose (in 102 days). Itraconazole was administered at 100 mg VO BID concomitant with amphotericin B, and then at 100 mg/day for a full year after the patient's release from the hospital. Hepatic, renal and cardiovascular functions were strictly monitored and no complications were noted except during the first days of therapy. During this period there was a discrete and transient increase in the level of liver enzymes and creatinine that disappeared by the end of the first week. Hydroelectrolytic balance remained under normal limits except for three episodes of hypokalemia that were successfully corrected with endovenous potassium chloride.
The pain and pruritus disappeared at the third week of treatment and lesions started to improve at the beginning of the sixth week of therapy. After the tenth week, fungal forms were not found on microscopic examination of control scrapings or biopsies. In addition, it was no longer possible to isolate the fungus in culture after six months, leading to the declaration of the clinical cure of the patient in accord with the Bayles and Queiroz-Telles criteria 4, 8, 9. The patient recovered the functionality of his leg and returned to his normal daily activities (Fig. 1C, 1D). After one year no new lesions developed and the agent was no longer isolated from control skin biopsies.
Chromoblastomycosis is a disease difficult to treat due to the marked chronicity of lesions and the well-known resistance of many of its etiologic agents to monotherapy 10. Prior to the advent of broad spectrum antifungal agents, Yanase and Yamada, as well as others in Japan, successfully treated cases of chromoblastomycosis caused by Fonsecaea pedrosoi through the local application of heat (thermal therapy) based upon the inability of the fungus to grow at temperatures beyond approximately 37–40°C 4, 11–13. Thermal therapy still remains an option to combine with oral and systemic antifungals in extensive and refractory cases 14, 15.
It is well known that there is no ideal effective therapy for chromoblastomycosis 6 and that treatment depends upon the etiologic agent and the severity of the clinical presentation 7. Concerning the latter, it is important to point out that the edema and dermal fibrosis which is often present in infections due to F. pedrosoi, can reduce the tissue levels of antifungals 4 which in turn diminishes the possibilities of successful therapy. In this respect, small incipient lesions, regardless of the causative agent, can be effectively treated with surgical excision as the first line of therapy, or alternatively with topical therapy, thermotherapy, electrodessication, cryotherapy, roentgenotheraphy, laser or liquid nitrogen 6, 7, 16. For extensive lesions such as the ones described in this case report, local therapy is practically ineffective, especially with infections caused by F. pedrosoi3, 8, 17.
Regarding the role of etiologic agents in effective treatment, it is known that they differ relative to their sensitivity to several types of antifungals, e.g. C. carrionii is more sensitive to antifungals than F. pedrosoi4. According to Borelli, neither ketoconazole nor amphotericine B have shown any efficacy against the phaeohyphomycetes 7. Nevertheless, some authors point out that a combination of amphotericin B and 5-fluorocytosine is one of the best alternatives 1, 18, 19, as confirmed recently with an unusual case of chromoblastomycosis caused by P. verrucosa and successfully treated with this combination 10 of antifungals.
Imidazoles have been extensively used, mainly ketoconazole (200–400 mg/day) and itraconazole (100–200 mg/day) without satisfactory results 1, 20, 21. However, itraconazole—a triazole—as monotherapy has been partially effective in infections due to C. carrionii1 but has to be combined with 5-fluorocytosine for effective treatment in cases due to F. pedrosoi1. Nonetheless recent trials using pulse itraconazole at 400 mg daily have demonstrated the effectiveness of this drug in treating cases caused by F. pedrosoi22 and even at doses between 100 and 200 mg in long term therapy as reported by Restrepo et al.23.
While therapy with Saperconazole—a fluorinated bis-triazole—was initiated some years ago and was found to be one of the most promising antifungal among the imidazoles 1, 24, 25, it was removed from the market due to the development of tumors in laboratory animals 26. The development of a new generation of azoles such as voriconazole and posaconazole, which are potent, broad spectrum triazole antifungals, opens new therapy options 27, 28. In vitro, dematiaceous fungi are very sensitive to these new antifungals 4, 29, 30, but their efficacy in human subcutaneous mycoses remains to be determined. Nevertheless, treatment with posaconazole has resulted in successful outcomes in patients with eumycetoma or chromoblastomycosis which were refractory to standard therapies 31. This antifungal agent is a lipophilic triazole that is structurally similar to itraconazole and has an expanded spectrum of activity including virtually all forms of pathogenic fungi 32. Possibly the oral suspension of posaconazole may offer better absorption than the capsule formulation of itraconazole but further pharmacokinetic studies and trials are needed to confirm this fact.
Terbinafine (an allylamine antifungal agent) 33, 34 has been reported to be one of the best therapies 15, 35, 36, with high efficacy in short time treatment of chronic lesions related to azole failures 35. However, results remain inconclusive until long term follow-up trials of case relapses are conducted.
It is worth to mentioning that combination of antifungals, as for example the combination of itraconazole to reduce the size of the lesions, with subsequent treatment of the remaining lesions with cryosurgery, represents a new alternative in the treatment of patients with large lesions 37, 38. On the other hand, the combination of itraconazole and terbinafine has also given acceptable results 14, 39.
Regarding susceptibility of the etiologic agent to drugs, itraconazole as monotherapy, administered at 50 to 400 mg daily for at least seven months, is recommended in the treatment of cases caused by C. carrionii. However, it is not recommended to treat chromoblastomycosis by F. pedrosoi unless it is associated to another antimycotic 7 as in the present case, in order to reduce the risk of generating resistance 40.
This case report is important because successful treatment was achieved with two drugs that in general are considered as only mildly effective when used as monotherapy and because there are little data in the literature regarding this combination therapy. The positive results may be the consequence of a possible synergism between both drugs which present different mechanisms of action. Amphotericin B created a permeabilization of the cytoplasmic membrane and loss of intracellular potassium, as well as a variety of other small molecules 41, 42, while itraconazole inhibited the enzymatic apparatus which catalyzes the C-alpha desmethilation of lanosterol which is a crucial step in ergosterol synthesis 41. We propose the use of this combination as an alternative therapy in cases involving severe, extensive lesions or when there is a lack of success with other therapeutic regimes.
Finally, since at present there are no comparative trials of antifungals in the treatment of chromoblastomycosis, there is a need to standardize the criteria regarding the evaluation of treatment of these infections. It is important to consider that as success of therapy is related to the causative agent involved and the severity of the disease, all cases should be individualized and managed on basis of a rational therapy.
We thank Dr Sofia Mata, Dr Mireya Mendoza and Dr Emilia Sordillo for the valuable academic advice and critical review of the manuscript. We are most grateful to the reviewers for their valuable critic review and precise commentaries on the article.