Chromoblastomycosis: combined treatment with pulsed itraconazole therapy and liquid nitrogen cryotherapy

Authors


Ranthilaka R. Ranawaka, MD 310/4 Kulasiri Kumarage Mawatha Katuwana, Homagama, Sri Lanka E-mail: ranthilaka37@yahoo.com

Abstract

Background  Three patients with histology- and culture-proven chromoblastomycosis reported to the Colombo South Teaching Hospital, Sri Lanka, in 2005. All three were men (age range, 48–53 years). The duration of symptoms varied from 1 to 8 years and the lesions were on the lower limbs.

Methods  The patients were treated simultaneously with liquid nitrogen cryotherapy and itraconazole pulses, i.e. 200 mg twice daily for 7 days per month, 1 week on and 3 weeks off. Cryotherapy was given every fortnight using large cotton swabs attached to ekels or the cryogun.

Results  Two patients showed a good clinical response within 4 months, with negative histopathology and culture in 4–6 months. The third patient was very resistant to treatment and needed a step-up of the itraconazole dose.

Conclusion  A combination of fortnightly liquid nitrogen cryotherapy and pulsed monthly itraconazole is cost-effective and shortens the duration of therapy compared with the use of itraconazole or cryotherapy alone.

Introduction

Chromoblastomycosis is a chronic fungal disease of the skin and subcutaneous tissues, caused by a group of dematiacaeous (black) fungi. It occurs worldwide, but most commonly in tropical and subtropical regions. Sri Lanka is a tropical country in which the fungus has been isolated from soil.1,2 Five causative fungi have been identified: Fonsecaea pedrosoi is the most prevalent, and Phialophora verrucosa, Cladosporium carrionii, Fonsecaea compacta, and Rhinocladiella aquaspersa occur in descending order of frequency. They vary in their specific morphologic characteristics of sporulation, which are evident on culture, but have only a single tissue form: pigmented sclerotic bodies, commonly called copper pennies, which are pathognomonic of chromoblastomycosis. The histology of the lesion shows a pseudo-epitheliomatous hyperplasia of the surface epithelium, microabscesses of neutrophils, and epithelioid and giant cell granulomas in the underlying dermis. Sclerotic bodies may present extracellularly or within giant cells and neutrophilic microabscesses.

Fibrosis may be a feature in long-standing cases.3–6 Complications, such as secondary infections, elephantiasis, and carcinomatous degeneration, may occur in chromoblastomycosis. The infection is usually introduced by trauma and is most often diagnosed in men engaged in agriculture.

Chromoblastomycosis is notoriously difficult to treat, with no one form of treatment being uniformly successful. Small lesions can be removed with wide and deep excision. Cryotherapy,7–10 topical heat therapy,11 systemic medications, and a combination of the above have been reported to be useful. Systemic medications are the most common method of treatment for widespread disease. Itraconazole, 200–400 mg daily, for a prolonged period, usually 8–12 months or longer, is the newest systemic antifungal found to be effective.12–16 Terbinafine, fluconazole, 5-flurocytocine, saperconazole, and amphotericin B have also been used.17–25

Materials and Methods

This was a prospective study performed to evaluate the efficacy of pulsed oral itraconazole (400 mg daily for 7 days per month) combined with liquid nitrogen cryotherapy in the treatment of chromoblastomycosis. The study protocol was reviewed and approved by the Ethical Review Committee, Sri Lanka Medical Association, Colombo, Sri Lanka.

The clinical diagnosis was confirmed by direct microscopy of skin scrapings in 20% KOH showing copper pennies, histologic appearance, and fungal culture on Sabouraud's glucose agar medium with cycloheximide and chloramphenicol. Liver transaminases were measured at screening and repeated every 3 months.

Patients were treated simultaneously with liquid nitrogen cryotherapy and pulsed itraconazole, i.e. 200 mg twice daily for 7 days per month, 1 week on and 3 weeks off.

Cryotherapy was given every fortnight using large cotton swabs attached to ekels or the cryogun. Liquid nitrogen cryotherapy was performed as two freeze–thaw cycles per site. Freezing was performed until a 1–2-mm white margin was formed around the site. The freezing times varied from 30 s to 2 min. The total thaw time and tissue temperature were not routinely recorded. The number of freezing cycles varied from 10 (small, localized lesions in Patient 1) to more than 20 (larger lesion in Patient 3). All three were treated as outpatients. The treatment was painful, but tolerable with oral pain killers given 30 min before the procedure. Local anesthesia was not used.

Clinical parameters, hyperkeratosis, erythema, and induration were noted for evaluation at each visit. The efficacy of therapy was judged by both clinical and mycologic response. Mycologic cure was defined as negative direct microscopy and culture. Clinical cure was defined as the absence of induration and hyperkeratosis, causing fibrosis and scarring of the lesion.

Results

Three men, aged 52, 53, and 48 years, with a clinical diagnosis of chromoblastomycosis were included in our study. All had verrucous lesions on the legs that had been present for 1, 5 and 8 years, respectively. All three patients were immunocompetent.

Patient 1 (Fig. 1a,b)

Figure 1.

(a) A 52-year-old male farmer with lesions on the right ankle at presentation. (b) Patient after 9 months of treatment

The first patient was a 52-year-old man, who had worked as a farmer for the last year. He was either barefoot or wore rubber slippers at work. He wore gloves, but never wore boots. He gave a history of minor trauma at the back of the right ankle 18 months earlier. Five months later he noticed a warty growth on the trauma site that later progressed into multiple satellite lesions. Individual lesions measured 1.5 × 2 × 1 cm (height). They were very itchy.

Three months following treatment, he showed a good clinical response and, after 4 months, microscopy and culture were negative. Nevertheless, his lesions were considered active on clinical examination as scaly plaques were present. Therefore, the same treatment was continued for a further 8 months until all the plaques were flattened. After a total of 12 months and nine itraconazole pulses, cure was obtained.

Patient 2 (Fig. 2a,b)

Figure 2.

(a) A 53-year-old male vegetable seller at presentation. (b) Patient after 11 months of liquid nitrogen cryotherapy and 10 itraconazole pulses

The second patient was a 53-year-old man, who was a vegetable seller. He collected vegetables growing in marshy land. On the trunks and leaves of the plants were small, sharp thorns. The man worked barefoot. He noticed a warty lesion on the dorsum of his left foot 6 years earlier. When the lesion reached 1.5 cm diameter in size, complete surgical excision was performed, but it recurred within 2 months. In 2003, he was treated with itraconazole, 200 mg every other day, for 1 year. In spite of a good clinical response, he defaulted on treatment because of financial constraints. In May 2005, he presented to the surgical department with the lesion shown in Fig. 2a. Histology showed a tuberculoid-type granulomatous reaction in the dermis, which was compatible with a tuberculoid ulcer. Tuberculosis screening was performed without positive results. [Erythrocyte sedimentation rate (ESR), 19 mm/h; normal chest X-ray; negative Mantoux test; sputum for acid-fast bacilli, negative (three times); hemoglobin, 13.1 g/dL). There was no past or contact history of tuberculosis. He was otherwise medically fit.

On presentation to our dermatology department (Fig. 2a), he had irreversible lymphedema; the lesion measured 4.5 × 3.3 × 0.5 cm (height). Chromoblastomycosis was confirmed by positive direct microscopy and culture.

Three months after treatment, the patient showed a good clinical response and, 4 months later, microscopy and culture were negative. After a total of 11 months and 10 itraconazole pulses, cure was obtained. His lesions healed with residual scarring.

Patient 3 (Fig. 3a,b)

Figure 3.

(a) A 48-year-old male shoemaker at presentation. (b) Patient after 10 months of liquid nitrogen cryotherapy and 16 itraconazole pulses

The third patient was a 48-year-old male shoemaker who wore rubber slippers only. He did not recall any trauma to the site. Ten years earlier, he noticed a warty lesion above the left ankle. In 1996, when the lesion was 2 cm in diameter, it was partially excised by a surgeon. In 2001, in spite of complete excision by a surgeon, it reappeared within 3 months. In 2001, he was treated with a combination of cryotherapy and terbinafine, but he defaulted on therapy after 6 months. In 2004, he was treated with itraconazole, 100 mg twice daily for 6 months, without response. In October 2005, he presented to our department with the lesion shown in Fig. 3a. At presentation, the lesion was 6 × 4 × 1.5 cm (height at the edge). The lesion had a very bad smell because of secondary bacterial infection.

Two months following intensive therapy, a poor response was noted. The patient also reported that the warty growth initially regressed after treatment and then re-grew at the end of the month. Therefore, itraconazole was increased to 200 mg twice daily for 7 days each fortnight (1 week on and 1 week off). Five months later, after eight itraconazole pulses, there was noticeable clinical improvement. Twelve months later, after 20 pulses, the edge of the lesion was active (Fig. 3b), although microscopy and culture were negative at 16 pulses and 10 months.

Discussion

The criteria for stopping systemic antifungal treatment and for achieving cure have not been determined experimentally. Therefore, the lesions were clinically assessed, and itraconazole pulses were continued until they were clinically inactive. Cryotherapy was continued until the verrucous lesions had become totally flattened.

Several reports have shown a good response of chromoblastomycosis to itraconazole as a single agent, but a long period of treatment, 18–30 months, is needed.12,13 Kumarasinghe and Kumarasinghe,14 from Sri Lanka, published the first study on the efficacy of itraconazole pulse therapy in chromoblastomycosis; subsequently, it has been confirmed by several studies.15

Severe pain, which lasted for more than 1 h after the procedure, was the main drawback of cryotherapy in our patients. Side-effects, such as pain, edema, and blistering, are inherent to cryosurgery with liquid nitrogen.8–10 To minimize these side-effects, cryotherapy was performed every fortnight.

In our patients, the skin lesions were less than 10 cm in the largest dimension. In two patients, the lesions had been present for 5 and 8 years, but the first patient presented within 1 year. The size of the lesion, period of evolution, and fungal species affect the efficacy of treatment. It was found that infection caused by Fonsecaea pedrosoi showed a slower and more resistant response to treatment.12 Although two patients showed a good response to the regime, the third patient was very resistant. With increased doses of fortnightly itraconazole pulses, the edge of the lesion was still active even after 20 pulses. Unfortunately, we could not determine the species in culture because of a lack of facilities.

Squamous cell carcinoma in chromic lesions or in the residual scar is a recognized complication. Recurrence is common in partially treated lesions. The patients will be followed up for 2 years after stopping therapy to assess the outcome.

Conclusions

A combination of fortnightly liquid nitrogen cryotherapy and pulsed monthly itraconazole is cost-effective and shortens the duration of therapy compared with the use of itraconazole or cryotherapy alone.