Paracoccidioidomycosis 

Updated: Apr 04, 2018
Author: Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH; Chief Editor: Michael Stuart Bronze, MD 

Overview

Practice Essentials

Paracoccidioidomycosis is a fungal infection endemic to South and Central America, most notably Brazil, Argentina, Colombia, and Venezuela (see the image below). It is caused by the thermally dimorphic fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii.[1] Although the infection is usually subclinical, the fungus can also cause chronic and severe disease.

Approximate distribution of paracoccidioidomycosis Approximate distribution of paracoccidioidomycosis in North, Central, and South America, based on case reports.

The 2 general clinical categories of paracoccidioidomycosis are (1) an acute/subacute form (juvenile paracoccidioidomycosis) and (2) a chronic form (adult paracoccidioidomycosis).

Signs and symptoms

Juvenile form

  • Lymphadenopathy and hepatosplenomegaly

  • Systemic symptoms - Include fever, weight loss, and malaise; present in most patients.

  • Symptoms related to lymph node enlargement, suppuration, and sinus tract formation

  • Multiple skin lesions

  • Mucous membrane and respiratory symptoms - These are unusual

Adult form

  • Primary lung infection - Cough (productive or nonproductive), dyspnea, malaise, fever, and weight loss are common symptoms

  • Chronic pulmonary sequelae - Develop in one third of patients; can include pulmonary fibrosis, bullae, and emphysematous changes that can contribute to pulmonary hypertension and cor pulmonale in 5% of cases.

  • Mucous membrane involvement - Occurs in 50% of patients with acute pulmonary infection; includes laryngeal and pharyngeal lesions

  • Oral lesions - May be associated with nasal and pharyngeal ulcers (Aguiar-Pupo stomatitis) and with mandibular or cervical lymph node enlargement

  • Cutaneous lesions - Caused by hematologic dissemination from the lungs; occur in 25% of patients; crusted papules, ulcers, nodules, plaques, and verrucous lesions are typical

  • Lymphadenopathy - Most common in the cervical region

Diagnosis

The diagnosis of paracoccidioidomycosis is most commonly made by visualization of the yeast cells in tissue, wet preparations (eg, sputum), or superficial scrapings (eg, skin lesions). Serological tests are available in areas of highest endemicity. In patients with active paracoccidioidomycosis, chest radiography reveals interstitial infiltrates (in 64% of cases) or mixed lesions with linear and nodular infiltrates.

Management

Systemic antifungal medications are the mainstay of medical management in paracoccidioidomycosis. Supportive measures and hospitalization may be warranted for patients with severe disease. If present, anemia and nutritional deficiencies should be treated. Antifungals effective against paracoccidioidomycosis include the following:

  • Triazoles - Itraconazole, voriconazole, and posaconazole; itraconazole is considered the drug of choice for paracoccidioidomycosis

  • Imidazoles - Ketoconazole

  • Sulfonamides - Sulfadiazine, trimethoprim/sulfamethoxazole

  • Amphotericin B - Reserved for severe cases of paracoccidioidomycosis that are refractory to other forms of therapy

Surgery

Occasionally, specific surgical treatments are warranted for life- or organ-threatening disease, such as neurosurgical procedures to relieve granuloma-induced spinal cord compression or hydrocephalus. Reconstructive surgery is sometimes needed to alleviate fibrotic sequelae.

Background

Paracoccidioidomycosis, formerly known as South American blastomycosis and Lutz-Splendore-Almeida disease, is a fungal infection endemic to South and Central America, most notably Brazil, Argentina, Colombia, and Venezuela (see the image below). (See Epidemiology.)

Approximate distribution of paracoccidioidomycosis Approximate distribution of paracoccidioidomycosis in North, Central, and South America, based on case reports.

Paracoccidioidomycosis is caused by the thermally dimorphic fungi Paracoccidioides brasiliensis and P lutzii.[1] Infection is usually subclinical. The fungus can proliferate, however, causing severe disease. (See Pathophysiology, Etiology, Prognosis, and Workup.)[2]

Paracoccidioidomycosis most commonly manifests as a chronic, progressive, systemic mycosis in men from the forested tropical and subtropical regions of Latin America. Pulmonary infection is the most common manifestation. Following dissemination, however, paracoccidioidomycosis frequently involves the mucous membranes (primarily of the oral cavity),[3] skin, and lymph nodes. (See Pathophysiology and Clinical Presentation.)

The 2 general clinical categories of paracoccidioidomycosis are (1) an acute/subacute form (juvenile paracoccidioidomycosis) and (2) a chronic form (adult paracoccidioidomycosis).

The following are noted for juvenile paracoccidioidomycosis:

  • Accounts for 5-10% of cases

  • Rapid progression after recent exposure

  • More common in children and adolescents

  • Tends to involve reticuloendothelial system with more severe disease

The following are noted for adult paracoccidioidomycosis:

  • Accounts for more than 90% of cases

  • Reactivation months to years after exposure

  • More common in adult males

  • Can be unifocal, affecting only 1 organ (lungs most commonly), or multifocal, affecting multiple organs

  • Lungs, mucous membranes, skin, and lymph nodes are most frequently involved

Paracoccidioides infection has been reported in the 9-banded armadillo, dogs, and other animals.[4, 5, 6] Animal-to-human transmission has not been reported. (See Pathophysiology and Etiology.)

Pathophysiology

Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis and P lutzii, thermally dimorphic fungi that grow as mycelium in nature and in culture at 18-23°C, and as yeast in human tissue and in culture at 37C°.[1] The lungs are the primary site of infection, likely secondary to inhalation of conidia or mycelial fragments.

After inhalation of the conidia, the fungus transforms into yeast cells within the alveolar macrophages. This transformation induces a nonspecific inflammatory response, which generally limits the disease at this point. Therefore, in most patients who are immunocompetent, the infection is asymptomatic and resolves without medical intervention. Less commonly, after an incubation period of weeks to decades, the fungus can disseminate through the venous and lymphatic systems, causing granulomatous disease in multiple tissues. (See the image below.)[7]

Granulomatous lesion involving the nose in patient Granulomatous lesion involving the nose in patient with paracoccidioidomycosis; note the resemblance to cutaneous leishmaniasis.

Direct inoculation of the skin or oral mucous membranes is not believed to be common but may result from the use of twigs to clean teeth, which is practiced in rural Brazil. The intestinal mucosa may serve as a site of direct inoculation if Paracoccidioides is ingested.

Cutaneous lesions can result from direct extension, hematogenous dissemination, or lymphatic dissemination.

Naturally acquired Paracoccidioides infection in animals has been reported only in armadillos. However, bats and saguis may serve as reservoirs. Animal-to-human and human-to-human transmissions do not appear to occur.

Etiology

Risk factors for paracoccidioidomycosis include the following[8] :

  • Agricultural work (especially coffee growers in Brazil) - The fungi are believed to reside in soil

  • Malnutrition

  • Smoking

  • Alcoholism

  • Immunodeficiency - Eg, from HIV/AIDS

Paniago et al found that the incidence of paracoccidioidomycosis in patients with HIV/AIDS was higher than that of the general population (1.5% vs 0.02%, respectively).[9, 10] Patients with AIDS are more likely to develop hematogenous dissemination and multiple organ involvement (juvenile-type disease).[11] Alcohol consumption and possibly tobacco smoking are also associated with disseminated disease.[12]

Otherwise-healthy patients who develop disseminated disease appear unable to mount a sufficient cellular immune response to the organism.

Epidemiology

United States

Paracoccidioides is not endemic to the United States, but paracoccidioidomycosis has been reported in North America and elsewhere in patients who had previously visited or resided in endemic areas.[13] These cases are believed to have resulted from reactivation of latent infection

Worldwide

Paracoccidioidomycosis is restricted geographically to South and Central America, from Mexico to Argentina, with the exception of Chile, Surinam, Guiana, Nicaragua, Belize, and most of the Caribbean islands.[8, 14]

Within endemic regions, paracoccidioidomycosis is restricted to coffee- or tobacco-growing areas, areas with acidic soils, and areas with temperatures between 12°C and 30°C, altitudes between 150 and 2000 m, and annual rainfall between 100 and 400 cm.

Of the 90 million people living in endemic areas, approximately 10 million are infected with Paracoccidioides, although exact figures are difficult to obtain.[15] Positive paracoccidioidin skin test results have been reported in 6-50% of people living in endemic areas, indicating prior exposure.

The highest incidence of the disease is in Brazil (approximately 80% of cases), followed by Colombia, Venezuela, Ecuador, and Argentina. Antibodies to P brasiliensis have been detected in 27% of blood donors in Brazil. (See the image below.)[16, 17, 18, 19]

Approximate distribution of paracoccidioidomycosis Approximate distribution of paracoccidioidomycosis in North, Central, and South America, based on case reports.

Sex-related demographics

The acute/subacute juvenile form of paracoccidioidomycosis affects both sexes equally, but the chronic, adult form of the disease affects men more frequently than women, with a reported ratio ranging from 6:1 to 15:1.

Paracoccidioides has receptors that bind estrogen. Binding of estrogen prevents the transformation of the mycelium into the yeast phase, which is necessary for tissue invasion.[20] This inhibition has been hypothesized to explain the sex differences in the occurrence of paracoccidioidomycosis, despite the fact that equal numbers of men and women have positive paracoccidioidin skin test results and that equal numbers of prepubertal boys and girls have the acute/subacute juvenile type.

Age-related demographics

The acute/subacute form of paracoccidioidomycosis is more common in children and adolescents. The chronic form of the disease is more common in adult males aged 30-50 years.

Prognosis

With appropriate antifungal therapy, most patients with paracoccidioidomycosis survive. Relapses are common, however, and patients must be evaluated regularly.

Complications of the disease include the following:

  • General - Malnourishment and anemia

  • Pulmonary - Hemoptysis, pulmonary fibrosis, and chronic cor pulmonale

  • Endocrine - Addison syndrome

  • Wound infection - Superinfection with bacteria or other fungal pathogens is always a concern in paracoccidioidomycosis because patients often have open wounds and an immune system that is already under stress. Superinfection can significantly complicate recovery or even lead to sepsis and death

  • Fibrosis - Complications in paracoccidioidomycosis generally result from fibrotic scarring that occurs during healing. Patients can have chronic, residual lung, oral, nasal, pharyngeal, and laryngeal problems after the lungs or mucous membranes heal. The destruction of mucous membranes can lead to perforation of the palate or nasal septum, while the destruction of the adrenal glands can cause Addison disease. Even with adequate treatment of paracoccidioidomycosis, the severe fibrosis that accompanies healing often results in long-term sequelae, such as disfiguring facial scarring, chronic dyspnea and cor pulmonale (from severe pulmonary fibrosis), and buccal atresia, dysphonia, and laryngeal and tracheal stenosis (from mucous membrane scarring)

Mortality

The mortality rate likely depends on the severity of the infection, organ systems involved, the age and sex of the patient, other comorbidities, and immune status (eg, the mortality rate is higher for patients with HIV).

A study in Brazil, where paracoccidioidomycosis has been reported as the eighth leading cause of death,[3] showed a mean mortality rate of 1.45 deaths per 1 million inhabitants and a nationwide, area-associated mortality rate of 3.73 deaths per 10,000 km2. Males tended to have a higher mortality rate than females.[21]

The mortality rate for children with acute paracoccidioidomycosis has been reported to be 7-10%.[22]

 

Presentation

History

Juvenile paracoccidioidomycosis

Findings in juvenile (acute/subacute) paracoccidioidomycosis can include the following:

  • Lymphadenopathy and hepatosplenomegaly (caused by reticuloendothelial system involvement)

  • Weight loss, fever, and malaise

  • Symptoms related to lymph node enlargement, suppuration, and sinus tract formation[23]

  • Multiple skin lesions

  • Mucous membrane and respiratory symptoms (unusual)

Patients with HIV infection may have a form of the disease that closely resembles the juvenile type.

Adult paracoccidioidomycosis

The adult (chronic) form of paracoccidioidomycosis accounts for 80-90% cases and represents endogenous reactivation years after initial contact with the fungus. Signs and symptoms include the following:

  • Primary lung infection - Cough (productive or nonproductive), dyspnea, malaise, fever, and weight loss are common symptoms; patients with pulmonary fibrosis secondary to paracoccidioidomycosis may present with minimal to no respiratory symptoms

  • Chronic pulmonary sequelae - Develop in one third of patients; can include pulmonary fibrosis, bullae, and emphysematous changes that can contribute to pulmonary hypertension and cor pulmonale in 5% of cases.

  • Mucous membrane involvement - Occurs in 50% of patients with acute pulmonary infection; includes laryngeal and pharyngeal lesions; results in dysphagia, dysphonia, stridor, and perioral granulomatous plaques; gingival involvement may lead to tooth loss

  • Oral lesions - May be associated with nasal and pharyngeal ulcers (Aguiar-Pupo stomatitis) and with mandibular or cervical lymph node enlargement

  • Cutaneous lesions - Caused by hematologic dissemination from the lungs; occur in 25% of patients; in rare cases, these lesions result from direct inoculation; crusted papules, ulcers, nodules, plaques, and verrucous lesions are typical

  • Lymphadenopathy - Most common in the cervical region, but all lymph node chains can be involved

Other sites of involvement include the following:

  • Adrenal glands - Affected in 48% of cases, with adrenal insufficiency occurring in 15% of patients and Addisonian crisis developing in 5-9% of patients; fatigue or skin darkening from Addison disease can occur

  • Long bones - Including the ribs, humeri, and clavicles

  • Mesenteric lymph nodes - Involvement can lead to bowel obstruction

  • Central nervous system - Symptoms include headache; in 10-25% of patients, involvement results in meningoencephalitis (as part of a disseminated syndrome); isolated meningitis or a spinal cord lesion can also occur, but only rarely

  • Gastrointestinal system - Involvement can cause abdominal pain

Physical Examination

Because the diagnosis of paracoccidioidomycosis is usually delayed, patients are typically malnourished and anemic at presentation.

Juvenile paracoccidioidomycosis

Findings for the juvenile form of paracoccidioidomycosis are as follows:

  • Lymph nodes - Lymphadenopathy is prominent; nodes may enlarge to such a point that infection with Paracoccidioides may be confused with leukemia or lymphoma; lymph nodes are often suppurate and form sinus tracts to the skin; mesenteric adenopathy may lead to bowel obstruction

  • Skin - Sinus tracts from underlying lymph node involvement may be seen

  • Mucous membranes - Mucosal involvement is rare

  • Respiratory - Pulmonary involvement is occasionally present

  • Other - Cachexia, hepatosplenomegaly, adrenal insufficiency, osteomyelitis, and gastrointestinal involvement

Adult paracoccidioidomycosis

Mucous membranes

Up to 70% of patients have oral, pharyngeal, and/or laryngeal involvement. Lesions typically ulcerate to a granular surface with small, hemorrhagic crusts; often this classic appearance is referred to as mulberrylike stomatitis. The lips, gingiva, palate, buccal mucosa, and tongue are commonly affected (see the image below). Laryngeal involvement may cause dysphonia. Mucosal lesions involving the ocular and genital regions occasionally occur.

Ulcerated nodule on the tongue in a man with parac Ulcerated nodule on the tongue in a man with paracoccidioidomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.

Skin

Lesions occur most commonly on the face and are polymorphic (see the image below). They may be papular, nodular, ulcerated, papillomatous, or even tuberous and most often arise from direct extension of mucous membrane lesions or underlying lymph node or bone involvement. Occasionally, hematogenous spread results in widely scattered, monomorphic lesions.

Crusted plaques over the central part of the face Crusted plaques over the central part of the face in a man with paracoccidioidomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.

Lymph nodes

Numerous visceral and subcutaneous nodes may be involved through hematogenous and lymphatic spread; cervical nodes are commonly affected. Nodes are hypertrophic, firm, and painful and can be suppurate, forming fistulas or ulcers in the skin.

Respiratory

Lung involvement occurs in 70-80% of patients. In 25% of patients with the adult type of disease, lungs are the only organ system involved. Chronic dyspnea, cough, and sputum production may develop.

Other

Signs and symptoms of the adult form of paracoccidioidomycosis can also include the following:

  • Hepatosplenomegaly - Caused by hepatic and splenic lesions; occurs in approximately 5% of cases

  • Central nervous system involvement - Meningitis and parenchymal granulomatous disease; observed in 5-25% of patients; can cause mental status changes and seizures[24]

  • Adrenal insufficiency

  • Bone and joint involvement

 

DDx

Diagnostic Considerations

Differential diagnosis in paracoccidioidomycosis includes the following disorders:

  • Blastomycosis

  • Lymphoma

  • Leukemia

  • Sporotrichosis

  • Wegener granulomatosis

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of paracoccidioidomycosis is most commonly made through the visualization of typical yeast cells in tissue, wet preparations (eg, sputum), or superficial scrapings (eg, skin lesions).[25] Cultures should be obtained, but are limited by low sensitivity. Cerebrospinal fluid (CSF) studies are nonspecific, and mycologic examination (smears and culture) is usually negative. Blood culture results are typically negative, but recovery of P lutzii from blood has recently been reported.[26]

Other laboratory studies

Patients with juvenile paracoccidioidomycosis can have anemia, hypergammaglobulinemia, and eosinophilia.

Pulmonary function tests

These may reveal obstructive abnormalities.

Microbiology

Wet mount of sputum or lesional material

In more than 90% of patients, potassium hydroxide (KOH) preparation of sputum or lesional material reveals large, multiple budding yeasts (blastoconidia) (2-30 µm in diameter) diagnostic for paracoccidioidomycosis. The typical pathognomonic features are large, thick-walled, spherical yeast cells with multiple peripheral buds encircling the central cell (pilot's wheel or mariner's wheel). This appearance helps to differentiate Paracoccidioides from Blastomyces dermatitidis and all other yeasts. (See the image below.)

Potassium hydroxide (KOH) preparation from pus; no Potassium hydroxide (KOH) preparation from pus; note the multiple budding and variation in cell size with Paracoccidioides.

Histologic findings

Histologic examination reveals a granulomatous reaction with epithelioid and giant cells in association with a severe inflammatory infiltrate. Yeast with the characteristic pilot's wheel configuration may be found within giant cells or free in the inflammatory infiltrate. In skin and mucous membrane lesions, pseudoepitheliomatous hyperplasia with intraepidermal abscesses may be seen. Caseous necrosis is seen within the lymph nodes. A diffuse tissue reaction is typically seen in the juvenile form.

Culture

Paracoccidioides can be recovered on fungal media (eg, Sabouraud dextrose agar) but may require 20-30 days for growth. The fungus grows as a mold at room temperature; conversion to the typical yeast form by growth at 35-37°C is required for confirmation of the diagnosis.

Serologic Diagnosis

Serologic testing is not available in the United States (or outside endemic areas) and may be negative in patients infected with P lutzii infection.

Immunodiffusion

Double-agar gel immunodiffusion can be used for screening, diagnosis, and treatment follow-up. The most-used test, with a sensitivity of greater than 80% and a specificity of more than 90%, it detects circulating Paracoccidioides antibodies.

Complement fixation test

This test is useful but technically cumbersome. It has a quantitative nature that allows evaluation of patient response to treatment, but it may cross-react with Histoplasma capsulatum antigens.

Counter immunoelectrophoresis

This test is similar to immunodiffusion with regard to sensitivity and specificity. Counter immunoelectrophoresis can be a useful test in endemic areas that are resource poor, as it does not require a power supply or buffers.

Solid-phase immunoassays

These tests (eg, enzyme-linked immunoassay [ELISA]) are used to detect circulating antibodies in the patient's serum. Most ELISA tests detect antibodies to gp43, and newer assays report a sensitivity of 95% and a specificity of 93%. Cross-reactivity is also possible in patients with histoplasmosis or lobomycosis.

Immunoblotting

These tests (eg, Western blot) detect circulating antibodies to gp43 in the serum in 100% of patients and circulating antibodies to gp70 in 96% of patients.

Novel and emerging technologies

Monoclonal antibodies to antigenic compounds of P brasiliensis have increased sensitivity. The antigen gP43 reacts with the sera of almost all patients infected with P brasiliensis, but it also shows positivity in patients with histoplasmosis. Because of specific protocols needed in the development and purification of the antigen, it is typically only used in a research setting or at larger referral centers.[1, 27]

Synthetic peptides mimicking P brasiliensis innate antigens have been studied as cheaper and more sensitive and specific alternatives to current serologic testing. However, they are still under investigation.

Polymerase chain reaction (PCR) diagnosis has been reported in experimental settings and holds the potential for a more sensitive and specific methodology for the diagnosis of paracoccidioidomycosis.

Skin test

The paracoccidioidin skin test, if available, provides little diagnostic value. A positive skin test result indicates prior exposure, but it does not necessarily indicate current disease. The test may be useful prognostically because the conversion from an anergic result to a positive result is associated with a good prognosis in patients with severe paracoccidioidomycosis. Skin testing may also be an excellent tool for epidemiologic study of this disease.[28]

Radiology

Juvenile paracoccidioidomycosis

Imaging to evaluate the extent of lymphadenopathy is warranted, and the patient should also be evaluated for possible obstruction or compression of structures secondary to lymphadenopathy. If clinically indicated, bone scanning can be performed to evaluate bone lesions.

Adult paracoccidioidomycosis

Chest radiography and chest CT scanning should be considered. Chronic paracoccidioidomycosis patients without respiratory symptoms may have lung fibrosis. Chest radiography may show a nodular-interstitial, bilateral, and diffuse lung infiltrate in chronic paracoccidioidomycosis.[29] CT scanning may also be useful.

If clinically indicated, CT scanning or magnetic resonance imaging (MRI) of the brain should be obtained to evaluate CNS involvement. Consider imaging suspected affected areas.[30]

Chest radiography

In patients with active paracoccidioidomycosis, chest radiography reveals interstitial infiltrates (in 64% of cases) or mixed lesions with linear and nodular infiltrates. Lesions are frequently bilateral and symmetrical.

Most changes occur in the central and basal portions of the lungs; the apices are usually spared. Cavities are frequent, but hilar adenopathy is rare.

Chronic pulmonary sequelae can present as fibrosis, bullae, and emphysematous areas. Chronic cor pulmonale can cause right ventricular hypertrophy.

CT scanning and MRI

CT scanning of the chest may help delineate disease and rule out coexisting pathology (eg, tuberculosis, malignancy). In CNS disease, features on CT and MRI scans are nonspecific and similar to those seen in other granulomatous diseases (solitary or multifocal parenchymal lesions).[30]

 

Treatment

Approach Considerations

Systemic antifungal medications are the mainstay of medical management in paracoccidioidomycosis. Supportive measures and hospitalization may be warranted for patients with severe disease. If present, anemia and nutritional deficiencies should be treated.

Pregnancy

Paracoccidioidomycosis is uncommon in women of childbearing age. In one case of paracoccidioidomycosis in pregnancy, P brasiliensis was found in the placenta, but the child was not infected.

Amphotericin B is the only antifungal medication in pregnancy category B that is effective against P brasiliensis. All of the other medications that are currently used are category C or D.

Patients with HIV/AIDS

Patients with AIDS acquire a form of paracoccidioidomycosis that resembles the subacute juvenile type. Widespread disease quickly develops, and the meninges are more commonly involved in patients with AIDS than in patients who do not have AIDS.

Paracoccidioidomycosis is an AIDS-associated opportunistic infection. However, the incidence is lower than that expected by comparison to other endemic fungal infections. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) for Pneumocystis jiroveci pneumonia prophylaxis and azoles (eg, fluconazole, itraconazole, ketoconazole) for oropharyngeal candidiasis prophylaxis in HIV-infected patients may aid in the reduction in disseminated paracoccidioidomycosis.

AIDS is seen primarily in urban areas, whereas paracoccidioidomycosis is found mainly in rural areas, possibly contributing to the fact that the rate of paracoccidioidomycosis occurrence is lower than expected.

The paracoccidioidin skin test is frequently negative in infected patients with AIDS.

Supportive care

Supportive care among patients with paracoccidioidomycosis includes the following:

  • Treatment of anemia

  • Improvement of diet

  • Ensuring patient rest

  • Advising the patient to stop smoking and consuming alcohol

Surgery

Occasionally, specific surgical treatments are warranted for life- or organ-threatening disease, such as neurosurgical procedures to relieve granuloma-induced spinal cord compression or hydrocephalus. Reconstructive surgery is sometimes needed to alleviate fibrotic sequelae.

Deterrence/prevention

No vaccine against Paracoccidioides has been developed, although several peptide vaccines have been studied. No known control measures prevent paracoccidioidomycosis.

Antifungal Treatment

Triazoles (itraconazole, voriconazole, posaconazole)

Itraconazole is considered the drug of choice for paracoccidioidomycosis, with a reported effectiveness of 95%. The course of therapy is typically 200 mg/day for 6 months. Itraconazole is considered superior to ketoconazole because of shorter treatment course, lower toxicity profile, and lower relapse rate (3-5%). Fluconazole is not typically used, because of its lower response rates and more frequent relapse.

Voriconazole, a newer azole agent, has in vitro activity against the yeast cells of P brasiliensis and has been shown in open-label trials to be an effective agent.[31] Another newer azole, posaconazole, has been used with reported success in this disease.

Imidazoles (ketoconazole)

Ketoconazole is also an effective agent for paracoccidioidomycosis, with a cure rate of 85-90% and an associated relapse rate of less than 10%. A dose of 200-400 mg/day in adults or 5 mg/kg/day in children for 6-18 months is required. Ketoconazole is associated with significant toxicities, including hepatic dysfunction and sex hormone alterations, as well as with many drug-drug interactions.

Sulfonamides (sulfadiazine, trimethoprim-sulfamethoxazole)

The maximum dose of sulfadiazine is 4 g/day in adults and 60-100 mg/kg/day in divided doses in children. Once clinical and mycologic response is evident, this dose can be cut in half. For long-acting compounds, the dosing is 0.5 g/day, following an initial dose of 1 g/day for 2-3 weeks. Patients should be treated for 3-5 years. This results in a 70% cure rate, but there is also a 30% relapse rate.

Trimethoprim-sulfamethoxazole (TMP-SMX) is typically dosed as one double-strength tablet (160 mg trimethoprim, 800 mg sulfamethoxazole) twice daily (8-10 mg/kg/day [based on trimethoprim] for children). Compared to itraconazole in a recent study, TMP-SMX treatment was associated with a 51% cure rate (versus 86% for itraconazole) with a median treatment time of 23 months (versus 12 months for itraconazole).[32]

Amphotericin B

Reserve this drug for severe cases of paracoccidioidomycosis that are refractory to other forms of therapy. Cumulative doses range from 1-2 g based on clinical response. The drug is not curative; therefore, maintenance therapy with a sulfonamide or an azole is subsequently required. Only the intravenous formulation of this drug is effective, but its use is limited because of associated toxicities. The associated rate of improvement and relapse rate are similar to those of sulfonamide.

Consultations

Consult an infectious disease specialist for difficult diagnoses, especially in nonendemic areas, and for patients who require long-term treatment with potentially toxic medications (eg, amphotericin B).

Consider the following consultations as well, depending on organ involvement and severity of disease:

  • Pulmonologist

  • Internal medicine specialist

  • Dermatologist

  • Surgeon

Long-Term Monitoring

During and after treatment for paracoccidioidomycosis with antifungal medications, patients must be regularly evaluated to ensure an adequate response to therapy and monitor for relapse.

Complement fixation tests can be used to track the response to therapy; antibody levels decrease with improvement. Complement fixation also can be used to detect relapse because antibody levels increase again. The new antibody tests directed against P brasiliensis antigenic glycoproteins may prove useful in monitoring disease activity and response to therapy.

Absence of symptoms for 2 years after antifungal therapy is considered by some to indicate a cure. Others believe that mycologically negative results in 3 specimens after the cessation of therapy indicate a cure.

 

Medication

Medication Summary

Antifungal medications are the mainstay of treatment for paracoccidioidomycosis. These include the following:

  • Itraconazole - The drug of choice[31, 33]

  • Ketoconazole

  • Fluconazole - Not as effective as either itraconazole or ketoconazole; its main advantages are that it is available in oral and intravenous forms and that it penetrates into the CSF well

  • Amphotericin B - Used in patients with severe disease; it is the only medication in this list in pregnancy category B; all of the other medications are in pregnancy category C or D.

  • Trimethoprim-sulfamethoxazole (TMP-SMZ) – Continues to be used because of low cost

  • Sulfadiazine - Also still used because of its low cost

Historically, the sulfonamides have been the most widely used medications for the treatment of paracoccidioidomycosis; their advantage is their low cost. However, relapses are more common with the sulfonamides than with other mediations, and longer courses of therapy may be required.

Reports have documented successful treatment of paracoccidioidomycosis with voriconazole, posaconazole, and terbinafine.[34] The following guidelines may be helpful: Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.

Antifungal agents

Class Summary

The mechanism of action may involve an alteration of RNA or DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Itraconazole (Sporanox, Onmel)

Itraconazole, a triazole antifungal agent, is preferred over the previously used agent ketoconazole because of reduced length of therapy and relapse rate. Adverse effects are also less frequent with itraconazole. This is a synthetic fungistatic triazole that inhibits cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

An intravenous formulation is available but no intravenous dose has been established for P brasiliensis treatment.

Ketoconazole

Imidazole is a broad-spectrum antifungal agent that inhibits the synthesis of ergosterol, a key fungal cell membrane component. This causes cellular components to leak, resulting in fungal cell death.

Amphotericin B, conventional

Amphotericin B is indicated for the treatment of life-threatening fungal infections or when oral antifungal medications cannot be tolerated. The drug is produced from a strain of Streptomyces nodosus. The antifungal activity of amphotericin B results from its ability to insert itself into the fungal cytoplasmic membrane at sites that contain ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium).

At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity. At higher concentrations, however, pores of 40-105 nm in are produced in the cytoplasmic membrane, leading to large losses of ions and other molecules.

A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Indeed, this may be the main fungicidal activity of amphotericin B.

Amphotericin B is not curative by itself; all patients treated with this drug require maintenance treatment with sulfonamide or an azole. Improvement occurs in 65-70% of patients treated with this agent.

Fluconazole (Diflucan)

Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents the conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. It is not considered the drug of choice in the treatment of paracoccidioidomycosis.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Trimethoprim and sulfamethoxazole (Septra DS, Bactrim, Bactrim DS)

Sulfamethoxazole competes with para-aminobenzoic acid (PABA) and thereby inhibits microbial synthesis of dihydrofolate. Trimethoprim binds to and reversibly inhibits the enzyme dihydrofolate reductase, thereby blocking the production of tetrahydrofolic acid from dihydrofolic acid. Thus, 2 consecutive steps in the synthesis of essential nucleic acids and proteins are blocked. TMP-SMZ is used to treat paracoccidioidomycosis in Central and South America primarily because of its low cost, but it is not the drug of choice.

Sulfadiazine

Therapy with sulfa agents is long term (3-5 y) and is associated with a high relapse rate (20-25%). Paracoccidioidomycosis is the only mycosis amenable to treatment with sulfa drugs.