Practice Essentials
Paracoccidioidomycosis is a fungal infection endemic to South and Central America, most commonly Brazil, Argentina, Colombia, and Venezuela (see the image below). It is caused by the thermally dimorphic fungi of the genus Paracoccidioides. [1] Although the infection usually is subclinical, the fungus also can cause chronic and severe disease.
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
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Lymphadenopathy and hepatosplenomegaly
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Systemic symptoms - Include fever, weight loss, and malaise; present in most patients.
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Symptoms related to lymph node enlargement, suppuration, and sinus tract formation
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Multiple skin lesions
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Mucous membrane and respiratory symptoms - These are unusual
Adult form
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Primary lung infection - Cough (productive or nonproductive), dyspnea, malaise, fever, and weight loss are common symptoms
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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.
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Mucous membrane involvement - Occurs in 50% of patients with acute pulmonary infection; includes laryngeal and pharyngeal lesions
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Oral lesions - May be associated with nasal and pharyngeal ulcers (Aguiar-Pupo stomatitis) and with mandibular or cervical lymph node enlargement
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Cutaneous lesions - Caused by hematologic dissemination from the lungs; occur in 25% of patients; crusted papules, ulcers, nodules, plaques, and verrucous lesions are typical
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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:
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Triazoles - Itraconazole, voriconazole, and posaconazole; itraconazole is considered the drug of choice for paracoccidioidomycosis
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Imidazoles - Ketoconazole
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Sulfonamides - Sulfadiazine, trimethoprim/sulfamethoxazole
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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 in North, Central, and South America, based on case reports.
Paracoccidioidomycosis is caused by the thermally dimorphic fungi of the genus Paracoccidioides. [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:
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Accounts for 5-10% of cases
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Rapid progression after recent exposure
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More common in children and adolescents
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Tends to involve reticuloendothelial system with more severe disease
The following are noted for adult paracoccidioidomycosis:
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Accounts for more than 90% of cases
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Reactivation months to years after exposure
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More common in adult males
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Can be unifocal, affecting only 1 organ (lungs most commonly), or multifocal, affecting multiple organs
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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, P americana, P restrepiensis, P venezuelensis 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 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
Paracoccidioidomycosis is caused by thermally dimorphic endemic fungi of the genus Paracoccidioides. Currently, 5 species have been recognized as the cause of this mycosis. [8] These include Paracoccidioides lutzii, and 4 species within the P brasiliensis species complex; P americana, P brasiliensis, P restrepiensis, and P venezuelensis. P brasiliensis, the most common species, is found in Brazil, Argentina, Paraguay, Peru and Venezuela. P americana is found predominantly in Brazil and Venezuela. P restrepiensis is chiefly found in Colombia, and P venezuelensis in Venezuela. P lutzii appears confined to northern and central Brazil.
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. [9] 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. [10, 11]
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. [12] 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.) [13, 14, 15, 16]
Approximate distribution of paracoccidioidomycosis in North, Central, and South America, based on case reports.
Risk factors
Risk factors for paracoccidioidomycosis include the following [10] :
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Agricultural work (especially coffee growers in Brazil) - The fungi are believed to reside in soil
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Malnutrition
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Smoking
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Alcoholism
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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). [17, 18] Patients with AIDS are more likely to develop hematogenous dissemination and multiple organ involvement (juvenile-type disease). [19] Alcohol consumption and possibly tobacco smoking are also associated with disseminated disease. [20]
Otherwise-healthy patients who develop disseminated disease appear unable to mount a sufficient cellular immune response to the organism.
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. [21] 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:
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General - Malnourishment and anemia
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Pulmonary - Hemoptysis, pulmonary fibrosis, and chronic cor pulmonale
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Endocrine - Addison syndrome
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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
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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. [22]
The mortality rate for children with acute paracoccidioidomycosis has been reported to be 7-10%. [23]
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Approximate distribution of paracoccidioidomycosis in North, Central, and South America, based on case reports.
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Granulomatous lesion involving the nose in patient with paracoccidioidomycosis; note the resemblance to cutaneous leishmaniasis.
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Potassium hydroxide (KOH) preparation from pus; note the multiple budding and variation in cell size with Paracoccidioides.
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Crusted plaques over the central part of the face in a man with paracoccidioidomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.
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Ulcerated nodule on the tongue in a man with paracoccidioidomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.
