Paracoccidioidomycosis (South American blastomycosis)

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Paracoccidioidomycosis (South American blastomycosis)

Wanda Sonia Robles and Mahreen Ameen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Paracoccidioidomycosis (PCM) is a chronic, progressive, granulomatous mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. It primarily affects the lungs and is believed to be acquired from inhalation of the fungus that resides in soil and plants of endemic regions. PCM is restricted to Latin America, where it is the most prevalent systemic endemic mycosis. It has been reported in nearly all countries from Mexico to Argentina, with the exception of the Caribbean islands and Chile. Eighty percent of cases occur in Brazil, with the highest incidence in the state of Sao Paulo. This is followed by Venezuela, Colombia, Ecuador, and Argentina. PCM characteristically affects those working in agriculture and in rural areas. Because of the long latency period, the disease may appear many years after a person has left an endemic region. Untreated PCM has one of the highest rates of mortality of all the systemic mycoses.

There are two main clinical forms: an acute or subacute form, and a unifocal or multifocal chronic form. The acute form affects young people of both sexes and involves mainly the reticuloendothelial system. This form of infection is often severe and carries a worse prognosis. The chronic form most commonly affects adult males, and causes pulmonary and/or mucocutaneous disease. Most cases of pulmonary infection have an indolent course. Only 2% of those infected develop the disseminated form of disease. Dissemination occurs most commonly to the mucosae of the upper airways and upper gastrointestinal tract. Cutaneous and lymph node involvement is common, and other organ systems may be involved such as the adrenal glands (causing Addison’s syndrome), bones, and central nervous system. Oral lesions affect the gingiva, the hard palate, lips, and tongue. Nasal and pharyngeal ulcers can give rise to dysphagia and dysphonia. Ulcerative lesions can be painful, and are characterized by a punctate vascular pattern over a granulomatous base. Cutaneous lesions are highly polymorphic, consisting of verrucous and ulcerative papules, plaques, and nodules. Centrofacial localization is typical and usually a result of dissemination of oral lesions. PCM is also characterised by massive and visible cervical and submandibular lymphadenopathy, which may progress to form abscesses with draining sinuses. Other lymph glands may also become enlarged. Primary mucocutaneous infection is rare, but can occur following direct inoculation of the skin or mucous membranes. It can arise from using twigs to clean the teeth, which is practiced in rural Brazil.

Disseminated infection is severe in the immunocompromised, including those co-infected with HIV. The mortality rate with HIV infection is high, ranging from 30% to 45%. However, the incidence of PCM in patients with AIDS in Latin America is low, and this has been attributed to the widespread use of trimethoprim–sulfamethoxazole as prophylaxis for Pneumocystis carinii pneumonia.

Management strategy

P. brasiliensis is highly sensitive to antifungal drugs, and therefore a large therapeutic armamentarium exists to treat PCM. Itraconazole is the drug of choice for the treatment of mild to moderate acute and chronic clinical forms of PCM. It is given at a dose of 100–200 mg daily for a mean period of 6 months (range 3–12 months) depending on clinical response. It gives a cure rate of 90%, and recurrence rates of 0-15% have been reported after a median of 12 months, depending on comorbidities such as alcoholism, malnutrition, and AIDS. Ketoconazole (200–400 mg daily) is also highly effective, 90% of patients responding after 6–12 months of treatment with only a 10% relapse rate. However, adverse effects are common especially with long-term treatment. With the availability of newer antifungals, its use has decreased. Sulfonamides (sulfadiazine, sulfamethoxypyridazine, sulfadimethoxine, trimethoprim–sulfamethoxazole) are an attractive option as they are inexpensive and well-tolerated. However, therapy duration is characteristically long, usually 2 to 3 years. Compliance can therefore be a problem, which might explain their lower cure rate of only 70%. In addition, they have a significant relapse rate of 35%. They are still commonly used as first agents in endemic regions because of their ready availability and low cost. Parenteral amphotericin B (cumulative dose of 1–2 g based on clinical response) is the drug of choice for severe or refractory infection. The cure rate is only 60%, but consideration must be given to the fact that it is usually given to the most severely ill patients. The relapse rate with amphotericin B is generally higher than with itraconazole, occurring in 20–30% of cases. Long-term maintenance therapy with an azole or sulfonamide is therefore required. In cases of central nervous system (CNS) PCM, sulfadiazine appears to be equally effective as amphotericin B. More recently, voriconazole, an extended-spectrum triazole, has demonstrated comparable efficacy and tolerability to itraconazole in the treatment of PCM. However, its high costs make it prohibitive for use in most endemic settings. There are few studies demonstrating the efficacy of fluconazole for PCM. It has been suggested that it may be useful in the management of CNS PCM given its excellent CNS penetration. Long-term follow-up after treatment of PCM is required as relapse rates are unknown.

Specific investigations

Rapid diagnosis may be achieved by direct microscopic examination of sputum or other exudates in potassium hydroxide. P. brasiliensis appears as large, round yeast cells with multiple budding. Culture of sputum, skin, lymph node, or bone marrow specimens on Sabouraud dextrose agar can recover the organism, but may require 20–30 days for growth. Biopsy specimens reveal granuloma formation, and Gomori methenamine silver stain reveals yeast cells. There are several serological tests which detect antibodies against the fungus, and they can provide results earlier than culture or histopathology. The most common test is immunodiffusion, which has high specificity but sensitivity varies depending on the type of antigen used. Therefore, a negative serologic response does not exclude PCM, particularly in the immunocompromised.

Paracoccidioidomycosis in patients with human immunodeficiency virus: review of 12 cases observed in an endemic region in Brazil.

Paniago AM, de Freitas AC, Aguiar ES, Aguiar JI, da Cunha RV, Castro AR, et al. J Infect 2005; 51: 248–52.

This study demonstrated that the lymph nodes were the organ most commonly involved (n=10, 83.3%), followed by the lung (n=7, 58.3%). Papulonodular ulcerative skin lesions affected 50% (n=6), and oral mucosal ulcerative lesions were present in 42% (n=5). A single patient had pleural involvement with a secondary pathological rib fracture. Seven patients had multi-organ involvement. All patients were treated with trimethoprim–sulfamethoxazole, and seven patients in addition received amphotericin B. However, eight patients (67%) died as a result of disease progression.

First-line therapies

imageItraconazole B
imageSulfonamides B
imageAmphotericin B B

Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis.

Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GM, Hoo S, Vaccari EH, et al. Med Mycol 2002; 40: 411–17.

This study from Brazil included 42 patients with moderately severe paracoccidioidomycosis. They were randomized to receive itraconazole 50–100 mg daily (n=14), ketoconazole 200–400 mg daily (n=14) or sulfadiazine 150 mg/kg daily (n=14) for an induction period of 4 to 6 months. This was followed by slow release sulfa (sulfamethoxypyridazine) until negative serological results were obtained. The majority of patients in all arms were reported as cured after 6 months of treatment, and antibody levels reduced significantly by 10 months of treatment for all three drugs.

This study demonstrated that both sulfadiazine and the azoles were equally effective, and the cure rates for the individual drugs were similar to previous studies.

Paracoccidioidomycosis in children: clinical presentation, follow-up and outcome.

Pereira RM, Bucaretchi F, Barison Ede M, Hessel G, Tresoldi AT. Rev Inst Med Trop Sao Paulo 2004; 46: 127–31.

This study from Brazil investigated 70 episodes of infection in 63 children under the age of 15 years (range 2–15 years). The juvenile and disseminated form of paracoccidioidomycosis was seen in 70% of episodes, most of them presenting with a febrile lymphoproliferative syndrome. The diagnosis was confirmed by lymph node biopsy (84%), bone biopsy (9%), and skin biopsy (7%). Treatment consisted of either sulfamethoxazole–trimethoprim monotherapy (n=50), sulfamethoxazole–trimethoprim combined with amphotericin B (n=9), or ketoconazole (n=5). Follow-up revealed significant sequential improvement 1 and 6 months later. However, six patients died (9.3%) and four developed sequelae: portal hypertension in three and hypersplenism in one (6.3%). The authors attribute the deaths to the severity of disseminated infection in the context of profound immunosuppression caused by paracoccidioidomycosis as well as malnutrition. A long period of drug treatment, up to 2 years, is required in order prevent any risk of relapse.

The authors suggest sulfamethoxazole–trimethoprim as first-line therapy in children because of its efficacy, low cost, and easy route of oral administration. It may also be infused intravenously for severe infection. They attributed therapy failure largely to non-compliance.

Paracoccidioidomycosis: a comparative study of the evolutionary serologic, clinical and radiologic results for patients treated with ketoconazole or amphotericin B plus sulfonamides.

Marques SA, Dillon NL, Franco MF, Habermann MC, Lastoria JC, Stolf HO, et al. Mycopathologia 1985; 89: 19–23.

This was a retrospective study comparing the use of ketoconazole (400 mg daily for 30 days followed by 200 mg daily for 18 months) in 22 patients against amphotericin B (1.5–1.75 mg/kg/day for 30–60 days) together with sulfonamide maintenance therapy for up to 18 months, in 32 patients. Approximately one-third of patients in each group had the acute form of the infection, and the rest had chronic disease. Patients treated with ketoconazole demonstrated better responses, but the results were not statistically significant. There was a sharper drop in antibody titers in patients treated with ketoconazole, but there was no difference in radiological evolution between the treatments.

Failure of amphotericin B colloidal dispersion in the treatment of paracoccidioidomycosis.

Dietze R, Flowler VG Jr, Steiner TS, Pecanha PM, Corey GR. Am J Trop Med Hyg 1999; 60: 837–9.

In this study four adults with the aggressive juvenile form of paracoccidioidomycosis were treated with amphotericin B colloidal dispersion. One patient was also co-infected with HIV. They all received a dose of 3 mg/kg/day for at least 28 days. Three patients, including the HIV-infected case, demonstrated a complete clinical response, but relapsed within 6 months. They were subsequently successfully treated with co-trimoxazole. The authors suggest possible reasons for failure might have been the dose, treatment duration, the drug formulation, inadequate drug delivery to sites of infection, and impaired host immunity. The authors also describe unpublished data on five further patients with chronic paracoccidioidomycosis treated with liposomal amphotericin 4 mg/kg/day. They also responded to treatment initially, but subsequently relapsed after treatment was stopped.

These results raise concerns about the use of short courses of lipid-based formulations to treat PCM. Further and larger studies are required to investigate their efficacy.

Second-line therapies

imageKetoconazole B
imageFluconazole B
imageVoriconazole B
imageTerbinafine E

An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis.

Queiroz-Telles F, Goldani LZ, Schlamm HT, Goodrich JM, Espinel-Ingroff A, Shikanai-Yasuda MA. Clin Infect Dis 2007; 45: 1462–9.

This multicentre study from Brazil investigated the efficacy, safety, and tolerability of voriconazole for the long-term treatment of acute or chronic paracoccidioidomycosis, with itraconazole as the control treatment. Patients were randomized (at a 2 : 1 ratio) to receive oral voriconazole (n=35) or itraconazole (n=18) for 6 to 12 months. Voriconazole was given at an initial loading dose of 800 mg in divided doses on day 1, followed by 200 mg twice daily. The dose of itraconazole was 100 mg twice daily. There was a satisfactory response rate in 88.6% of the voriconazole group and 94.4% of the itraconazole group. The response rate among treatment-evaluable patients was 100% for both treatment groups. No relapses were observed after 8 weeks of follow-up. Both drugs were well tolerated although liver function test values were slightly higher in patients receiving voriconazole, necessitating the withdrawal of voriconazole from two patients.

This study has demonstrated equal efficacy and tolerability of oral voriconazole and itraconazole for the long-term treatment of paracoccidioidomycosis. This study also included a case of CNS paracoccidioidomycosis which responded to treatment. Voriconazole demonstrates good CNS penetration having been successfully used in the treatment of other mycotic CNS infections. On the basis of these results the authors suggested that intravenous voriconazole should be evaluated as an alternative to amphotericin B for the initial treatment of severe paracoccidioidomycosis, given the high relapse rate and toxicity associated with amphotericin B therapy.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Paracoccidioidomycosis (South American blastomycosis)

Wanda Sonia Robles and Mahreen Ameen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Paracoccidioidomycosis (PCM) is a chronic, progressive, granulomatous mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. It primarily affects the lungs and is believed to be acquired from inhalation of the fungus that resides in soil and plants of endemic regions. PCM is restricted to Latin America, where it is the most prevalent systemic endemic mycosis. It has been reported in nearly all countries from Mexico to Argentina, with the exception of the Caribbean islands and Chile. Eighty percent of cases occur in Brazil, with the highest incidence in the state of Sao Paulo. This is followed by Venezuela, Colombia, Ecuador, and Argentina. PCM characteristically affects those working in agriculture and in rural areas. Because of the long latency period, the disease may appear many years after a person has left an endemic region. Untreated PCM has one of the highest rates of mortality of all the systemic mycoses.

There are two main clinical forms: an acute or subacute form, and a unifocal or multifocal chronic form. The acute form affects young people of both sexes and involves mainly the reticuloendothelial system. This form of infection is often severe and carries a worse prognosis. The chronic form most commonly affects adult males, and causes pulmonary and/or mucocutaneous disease. Most cases of pulmonary infection have an indolent course. Only 2% of those infected develop the disseminated form of disease. Dissemination occurs most commonly to the mucosae of the upper airways and upper gastrointestinal tract. Cutaneous and lymph node involvement is common, and other organ systems may be involved such as the adrenal glands (causing Addison’s syndrome), bones, and central nervous system. Oral lesions affect the gingiva, the hard palate, lips, and tongue. Nasal and pharyngeal ulcers can give rise to dysphagia and dysphonia. Ulcerative lesions can be painful, and are characterized by a punctate vascular pattern over a granulomatous base. Cutaneous lesions are highly polymorphic, consisting of verrucous and ulcerative papules, plaques, and nodules. Centrofacial localization is typical and usually a result of dissemination of oral lesions. PCM is also characterised by massive and visible cervical and submandibular lymphadenopathy, which may progress to form abscesses with draining sinuses. Other lymph glands may also become enlarged. Primary mucocutaneous infection is rare, but can occur following direct inoculation of the skin or mucous membranes. It can arise from using twigs to clean the teeth, which is practiced in rural Brazil.

Disseminated infection is severe in the immunocompromised, including those co-infected with HIV. The mortality rate with HIV infection is high, ranging from 30% to 45%. However, the incidence of PCM in patients with AIDS in Latin America is low, and this has been attributed to the widespread use of trimethoprim–sulfamethoxazole as prophylaxis for Pneumocystis carinii pneumonia.

Management strategy

P. brasiliensis is highly sensitive to antifungal drugs, and therefore a large therapeutic armamentarium exists to treat PCM. Itraconazole is the drug of choice for the treatment of mild to moderate acute and chronic clinical forms of PCM. It is given at a dose of 100–200 mg daily for a mean period of 6 months (range 3–12 months) depending on clinical response. It gives a cure rate of 90%, and recurrence rates of 0-15% have been reported after a median of 12 months, depending on comorbidities such as alcoholism, malnutrition, and AIDS. Ketoconazole (200–400 mg daily) is also highly effective, 90% of patients responding after 6–12 months of treatment with only a 10% relapse rate. However, adverse effects are common especially with long-term treatment. With the availability of newer antifungals, its use has decreased. Sulfonamides (sulfadiazine, sulfamethoxypyridazine, sulfadimethoxine, trimethoprim–sulfamethoxazole) are an attractive option as they are inexpensive and well-tolerated. However, therapy duration is characteristically long, usually 2 to 3 years. Compliance can therefore be a problem, which might explain their lower cure rate of only 70%. In addition, they have a significant relapse rate of 35%. They are still commonly used as first agents in endemic regions because of their ready availability and low cost. Parenteral amphotericin B (cumulative dose of 1–2 g based on clinical response) is the drug of choice for severe or refractory infection. The cure rate is only 60%, but consideration must be given to the fact that it is usually given to the most severely ill patients. The relapse rate with amphotericin B is generally higher than with itraconazole, occurring in 20–30% of cases. Long-term maintenance therapy with an azole or sulfonamide is therefore required. In cases of central nervous system (CNS) PCM, sulfadiazine appears to be equally effective as amphotericin B. More recently, voriconazole, an extended-spectrum triazole, has demonstrated comparable efficacy and tolerability to itraconazole in the treatment of PCM. However, its high costs make it prohibitive for use in most endemic settings. There are few studies demonstrating the efficacy of fluconazole for PCM. It has been suggested that it may be useful in the management of CNS PCM given its excellent CNS penetration. Long-term follow-up after treatment of PCM is required as relapse rates are unknown.

Specific investigations

Rapid diagnosis may be achieved by direct microscopic examination of sputum or other exudates in potassium hydroxide. P. brasiliensis appears as large, round yeast cells with multiple budding. Culture of sputum, skin, lymph node, or bone marrow specimens on Sabouraud dextrose agar can recover the organism, but may require 20–30 days for growth. Biopsy specimens reveal granuloma formation, and Gomori methenamine silver stain reveals yeast cells. There are several serological tests which detect antibodies against the fungus, and they can provide results earlier than culture or histopathology. The most common test is immunodiffusion, which has high specificity but sensitivity varies depending on the type of antigen used. Therefore, a negative serologic response does not exclude PCM, particularly in the immunocompromised.

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