Etiology

Paracoccidioidomycosis (South American or Brazilian blastomycosis, Lutz-Splendore-Almeida disease) is an uncommon fungal infection endemic in South America, with cases reported in Central America and Mexico. The etiologic agent, Paracoccidioides brasiliensis, is a thermally dimorphic fungus found in the environment in the mycelial (mold) form and in tissues as yeast.

Epidemiology

P. brasiliensis is ecologically unique to Central and South America. Endemic outbreaks occur mainly in the tropical rain forests of Brazil, with cases scattered in Argentina, Colombia, and Venezuela. There is an increased incidence in areas with moderately high altitude, with high humidity and rainfall, and where coffee and tobacco are grown. Armadillos appear to be a natural reservoir for P. brasiliensis. The most common route of infection is by inhalation of conidia. The disease is not usually thought to be contagious, and person-to-person transmission has not been confirmed. Paracoccidioidomycosis is more common among boys after puberty due to the role of estrogen in preventing the transition of conidia to the yeast form.

Pathogenesis

The entry route into the body is via the respiratory tract, and the lungs are the site of primary infection, although not all patients have respiratory symptoms. Once the conidia reach the alveoli, yeast transformation takes place. The infection then spreads to the mucous membranes of the nose, mouth, and gastrointestinal tract. Cell-mediated immunity, specifically a T_H2-type response, is crucial to containing the infection. TNF-α and IFN-γ activated macrophages are responsible for intracellular killing of P. brasiliensis. The yeast can disseminate by the lymphohematogeneous route to skin, lymph nodes, and other organs and remain dormant in lymph nodes, producing a latent infection with reactivation occurring later on in life. There are cases of patients who developed disease 30 or more years after leaving an endemic region.

Histopathologically, the yeastlike cells are round, with the parent cell being quite large and surrounded by small buds, giving it the appearance of a ship’s wheel. A mixed suppurative and granulomatous inflammatory reaction with areas of necrosis are seen in pulmonary infections. In chronic infections fibrosis and calcification may be seen. Mucocutaneous infections are typified by ulceration and pseudoepitheliomatous hyperplasia.

Clinical Manifestations

There are 2 clinical forms of disease. The acute form is rare, occurs almost exclusively in children and persons with impaired immunity, and targets the reticuloendothelial system. Pulmonary symptoms may be absent, although chest radiographs often show patchy, confluent, or nodular densities. Patients typically present acutely with fever, malaise, wasting, lymphadenopathy, and abdominal enlargement from intra-abdominal lymphadenopathy. Hepatomegaly and splenomegaly are nearly constant. Localized bony lesions have been reported in children and can progress to systemic disease. Multifocal osteomyelitis, arthritis, and pericardial effusions can also occur. Nonspecific laboratory findings include anemia, eosinophilia, and hypergammaglobulinemia. Acute paracoccidioidomycosis has a 25% mortality rate.

Adults develop a chronic, progressive illness that manifests initially with flulike symptoms, fever, and weight loss. Pulmonary infection develops with dyspnea, cough, chest pain, and hemoptysis. Findings on physical examination are scant, although chest radiographs can show infiltrates that are disproportionate with mild clinical findings. Mucositis involving the mouth and its structures as well as the nose can manifest as localized pain, change in voice, or dysphagia. Lesions can extend beyond the oral cavity onto the skin. Generalized lymphadenopathy, hepatosplenomegaly, and adrenal involvement can lead to Addison disease. Meningoencephalitis and central nervous system granulomas can occur as presenting or secondary symptoms. Adults with extensive exposure to soil, such as farmers, are most likely to develop the chronic form of the disease.

Diagnosis

Demonstration of the fungus by direct wet mount (potassium hydroxide) preparation of sputum, exudate, or pus supports the diagnosis in many cases. Histopathologic examination of biopsy specimens using special fungal staining techniques is also diagnostic. Immunohistochemistry using monoclonal antibodies to specific glycoproteins can also be done on tissue sections. Culture of the fungus on Sabouraud-dextrose or yeast extract agar confirms the diagnosis. Antibodies to P. brasiliensis can be demonstrated in most patients. Serial antibody titers and lymphocyte proliferative responses to fungal antigens are useful for monitoring the response to therapy. The 43,000 kd glycoprotein (gp43) is present in sera of >90% of patients with paracoccidioidomycosis by immunodiffusion and in 100% by immunoblotting. Newer diagnostic methods that might prove to be very useful in the future include polymerase chain reaction, detection of gp43, and capture enzyme-linked immunosorbent assay to detect specific immunoglobulin E in patient sera. Skin testing with paracoccidioidin is not reliable, because 30-50% of patients with active disease are nonreactive initially and a positive test indicates previous exposure but not necessarily active disease.

Treatment

Itraconazole (5-10 mg/kg/day with maximum dosage of 400 mg/day) orally for 6 mo is the treatment of choice for paracoccidioidomycosis. Fluconazole has also been used, but high doses (≥600 mg/day) and longer treatment periods are required. Terbinafine, an allylamine, has potent in vitro activity against P. brasiliensis and has been used for successful treatment of paracoccidioidomycosis unresponsive to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) (8-10 mg/kg/day). Amphotericin B is recommended for disseminated disease and if other therapies fail. Therapy with sulfonamide compounds, including sulfadiazine, TMP-SMX, and dapsone, have been used historically and are generally less expensive than the newer azoles and allylamines. The primary disadvantage is that the treatment course is very long, lasting months to years, depending on the agent selected. Relapse can occur following any form of therapy, including with amphotericin B.

Two therapies currently under investigation include the use of curcumin, an antioxidant found in the Indian spice turmeric, and the calcineurin inhibitor cyclosporine A. Curcumin was found to have more antifungal activity than fluconazole against P. brasiliensis when studied in vitro using human buccal epithelial cells. Cyclosporine A has been shown to block the thermodimorphism of P. brasiliensis. Animal models have demonstrated that both DNA and peptide vaccines have great potential toward the development of a vaccine for use in humans.