South American blastomycosis or paracoccidioidomycosis is a serious, systemic mycotic infection caused by the thermally dimorphic fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii.[1] It is endemic to countries in Central and South America, most notably Brazil, Argentina, Colombia, and Venezuela. Infection is usually subclinical; however, the fungus can proliferate, causing severe disease.[2]
The 2 general clinical categories of South American blastomycosis are (1) an acute/subacute form (juvenile paracoccidioidomycosis) and (2) a chronic form (adult paracoccidioidomycosis).
The following is noted for the acute/subacute form (juvenile paracoccidioidomycosis):
Accounts for 5-10% of cases
Rapid progression after recent exposure
More common in children and adolescents
Tends to involve reticuloendothelial lymphatic system with more severe disease
The following is noted for the chronic form (adult paracoccidioidomycosis):
Accounts for more than 90% of cases
Reactivation months to years after exposure
More common in adult males
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.[3, 4, 5] Animal-to-human transmission has not been reported.
Also see Pediatric Blastomycosis and Blastomycosis (pulmonology).
Paracoccidioides is a thermally dimorphic fungus that grows as a mycelium in nature and in culture at 18-23C°. It grows as a yeast in human tissue and in culture at 37C°.
After inhalation of the conidia, the fungus transforms into yeast cells within the alveolar macrophages. 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, causing granulomatous disease in multiple tissues.[6]
Paracoccidioides is not endemic to the United States. A number of cases have been reported in patients who previously visited or resided in endemic areas.[7]
International
Paracoccidioides is endemic to Central and South America, with approximately 80% of cases occurring in Brazil. Positive paracoccidioidin skin test results have been reported in 6-50% of people living in endemic areas, indicating prior exposure. Antibodies to P brasiliensis have been detected in 27% of blood donors in Brazil.[8, 9, 10, 11] Of the 90 million people living in endemic areas, approximately 10 million are infected, although exact figures are difficult to obtain.[12]
Mortality/Morbidity
The mortality rate likely depends on the severity of the infection, organ systems involved, age of the patient, sex of the patient, other comorbidities, and immune status.
One study in Brazil showed a mean mortality rate of 1.45 deaths per 1 million inhabitants and an overall nationwide mortality rate per area of 3.73 deaths per 10,000 km2. Males tended to have a higher mortality rate than females.[13]
The mortality rate is higher for patients with HIV.
The mortality rate for children with acute paracoccidioidomycosis has been reported to be 7-10%.[14]
Complications generally result from fibrotic scarring that occurs during healing. Patients can have residual chronic lung, oral, nasal, pharyngeal, and laryngeal problems after the lungs or mucous membranes heal. If internal organs such as the adrenal glands are affected, chronic organ dysfunction (Addison disease) can develop.
Sex
The acute/subacute juvenile form of paracoccidioidomycosis affects both sexes equally.
The chronic adult form of paracoccidioidomycosis affects men more frequently than women, with a reported ratio ranging from 6:1 to 15:1. The fungus has receptors that bind estrogen. Binding of estrogen prevents the transformation of the mycelium into the yeast phase, which is necessary for tissue invasion. This inhibition has been hypothesized to explain the sex differences, 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
The acute/subacute form of paracoccidioidomycosis is more common in children and adolescents.
The chronic form of paracoccidioidomycosis is more common in adult males aged 30-50 years.
After the inhalation of conidia, the fungus transforms into yeast cells inside the alveolar macrophages. This transformation induces a nonspecific inflammatory response, which generally limits the disease at this point. Most patients are asymptomatic. However, more severe disseminated disease can occur.
South American blastomycosis (paracoccidioidomycosis) is categorized into 2 clinical forms: (1) acute/subacute (juvenile paracoccidioidomycosis) and (2) chronic (adult paracoccidioidomycosis)
Acute/subacute (juvenile paracoccidioidomycosis) findings are as follows:
Severe form of disseminated paracoccidioidomycosis occurring most commonly in children and adolescents
Fever, asthenia, anorexia, malaise, weight loss, and diarrhea
Symptoms related to lymph node enlargement, suppuration, and sinus tract formation
Mucous membrane and respiratory symptoms are unusual
Patients with HIV infection may have a form of the disease that closely resembles the acute/subacute juvenile type
Chronic (adult paracoccidioidomycosis) findings are as follows:
Chronic progressive form of paracoccidioidomycosis occurring most commonly in adult males
Slowly progressive disease; symptoms can occur months to decades after primary infection
Can be unifocal, affecting only one organ (lungs most common) or multifocal, affecting multiple organs
Low-grade fever, malaise, and weight loss
Mucous membrane symptoms may include pain with eating or drinking secondary to oral ulcerations; laryngeal and pharyngeal lesions can cause dysphagia, hoarseness, or stridor
Respiratory symptoms most commonly include cough and dyspnea; cough can be either dry or productive; patients with pulmonary fibrosis secondary to paracoccidioidomycosis may present with minimal to no respiratory symptoms
Symptoms secondary to other organ involvement can include abdominal pain from gastrointestinal involvement, headache from central nervous system involvement, and fatigue or skin darkening from Addison disease secondary to adrenal involvement
Paracoccidioides infection has been reported in the 9-banded armadillo, dogs, and other animals.[3, 4, 5] Animal-to-human transmission has not been reported.
Findings for the acute/subacute juvenile form of South American blastomycosis (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 can occasionally occur
Other - Cachexia, hepatosplenomegaly, adrenal insufficiency, osteomyelitis, gastrointestinal involvement
Findings for the chronic adult form of South American blastomycosis (paracoccidioidomycosis) are as follows:
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; lips, gingiva, palate, buccal mucosa, and tongue are commonly affected (see image below); laryngeal involvement may cause dysphonia; mucosal lesions involving the ocular and genital regions occasionally occur
View Image
Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlo....
Skin - Lesions occur most commonly on the face and are polymorphous (see image below); may be papular, nodular, ulcerated, papillomatous, or even tuberous; 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
View Image
Crusted plaques over the central part of the face in a man with South American blastomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatolog....
Lymph nodes - Lymphadenopathy; 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 chronic adult type of disease, lungs are the only organ system involved; chronic dyspnea, cough, and sputum production may develop
Other - Hepatosplenomegaly, caused by hepatic and splenic lesions, occurs in approximately 5% of cases; central nervous system involvement, both meningitis and parenchymal granulomatous disease, is observed in 5-25% of patients and can cause mental status changes and seizures[15] ; adrenal glands may become involved, leading to adrenal insufficiency; bone and joint involvement may be seen
Inhalation of the fungus P brasiliensis or Plutzii causes South American blastomycosis (paracoccidioidomycosis). Cutaneous lesions can result from direct extension, hematogenous dissemination, or lymphatic dissemination. Direct inoculation of skin or mucosal surfaces is rare. Animal-to-human and human-to-human transmissions do not appear to occur.
Paracoccidioidomycosis is more common in agricultural workers; the fungi are believed to reside in soil.
Alcohol consumption and possibly tobacco smoking are associated with disseminated disease.[16]
Paracoccidioidomycosis has been identified as an AIDS-associated opportunistic infection. Patients with AIDS may have a form of the disease that closely resembles the acute/subacute juvenile type.[17]
Otherwise-healthy patients who develop disseminated disease appear unable to mount a sufficient cellular immune response to the organism.
The criterion standard for diagnosis of South American blastomycosis (paracoccidioidomycosis) is visualization of the yeast cells in tissue, wet preparations, or superficial scrapings. The microscopic examination demonstrates thick-walled spherical yeast cells with multiple peripheral buds encircling a mother cell (pilot's wheal or mariner's wheal).
Culturing
Culture should always be ordered, but it has low sensitivity. Cultures on Sabouraud agar at room temperature grow mold in 3-4 weeks. Subcultures on rich media at 37°C grow the characteristic yeast form.
Skin testing
The paracoccidioidin skin test is available but has 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.
Serologic testing
Double-agar gel immunodiffusion can be used for screening, diagnosis, and treatment follow-up. It is the most–used test, with a sensitivity of greater than 80% and a specificity of greater than 90%.
With enzyme-linked immunosorbent assay and Western blot, the specificity depends on the antigen used.
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 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]
Serologic testing may be negative in patients infected with P lutzii.
Synthetic peptides mimicking P brasiliensis innate antigens have been studied as a cheaper and more sensitive and specific alternatives to current serologic testing. The synthetic peptide, P2, has been recently studied. These synthetic peptides are still under investigation.
Other laboratory studies
Patients with acute/subacute paracoccidioidomycosis can have anemia, hypergammaglobulinemia, and eosinophilia.
Imaging to evaluate the extent of lymphadenopathy is warranted; evaluate for possible obstruction or compression of structures secondary to lymphadenopathy. If clinically indicated, bone scanning can be performed to evaluate bone lesions.
Chronic 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.[18] CT scanning may be useful. If clinically indicated, CT scanning or MRI of the brain should be obtained to evaluate central nervous system involvement.
Histologic examination reveals a granulomatous reaction with epithelioid and giant cells in association with a severe inflammatory infiltrate. Spores with the characteristic pilot's wheel may be found within giant cells or free in the inflammatory infiltrate. In skin and mucous membrane lesions, pseudoepitheliomatous hyperplasia with intraepidermal abscesses occurs. Caseous necrosis is seen within the lymph nodes.
Systemic antifungal medications are the mainstay of medical management in South American blastomycosis (paracoccidioidomycosis). Supportive measures and hospitalization may be warranted for patients with severe disease. If present, anemia and nutritional deficiencies should be treated.
Special considerations
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 infection/AIDS
Patients with AIDS acquire a form of paracoccidioidomycosis that resembles the subacute juvenile type. Widespread disease quickly develops. The meninges are more commonly involved in patients with AIDS than in patients who do not have AIDS.
In recent years, paracoccidioidomycosis has been recognized as an AIDS-associated opportunistic infection. However, the incidence is lower than that expected by comparison to other endemic fungal infections. The use of trimethoprim and sulfamethoxazole (TMP-SMZ) for Pneumocystis pneumonia prophylaxis and ketoconazole for oropharyngeal candidiasis prophylaxis in HIV-infected patients may aid in the reduction in disseminated paracoccidioidomycosis.
AIDS is primarily seen in urban areas, whereas paracoccidioidomycosis is seen primarily in rural areas, possibly contributing to the lower than expected rate of disease.
The paracoccidioidin skin test is often negative in infected AIDS patients. levels of circulating antibodies to P brasiliensis are often low and, therefore, inaccurate in patients with AIDS.
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.
Antifungal medications are the mainstay of treatment for South American blastomycosis (paracoccidioidomycosis). Itraconazole, ketoconazole, fluconazole, amphotericin B, trimethoprim and sulfamethoxazole (TMP-SMZ), and sulfadiazine have all been successfully used to treat paracoccidioidomycosis.[19] Itraconazole is the drug of choice.[20, 21]
Historically, the sulfonamides have been the most widely used medications for the treatment of P braziliensis; 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.
Fluconazole is not as effective as either itraconazole or ketoconazole. Its main advantages are that it is available in both oral and intravenous forms and that it penetrates into the cerebrospinal fluid well.
Amphotericin B is used in patients with severe disease. Amphotericin B is the only medication in this list in pregnancy category B; all the other medications are pregnancy category C or D.
At this time, sulfadiazine and TMP-SMZ are still used for paracoccidioidomycosis because of their low cost.
Reports have documented successful treatment with voriconazole, posaconazole, and terbinafine.[22]
These guidelines may be helpful: Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.
Clinical Context:
Itraconazole is considered the drug of choice. It is as triazole antifungal agent that blocks the synthesis of ergosterol, an integral component of the fungal cell membrane. An intravenous formulation is available but no intravenous dose has been established for P brasiliensis treatment.
Clinical Context:
Ketoconazole has fungistatic activity. It is a midazole broad-spectrum antifungal agent that inhibits the synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death.
Clinical Context:
Amphotericin B is an antifungal agent that binds to sterols in the fungal cell membrane. Binding changes membrane permeability, which causes intracellular components to leak out of fungal cells. It is indicated for the treatment of life-threatening fungal infections or when oral antifungal medications cannot be tolerated.
Clinical Context:
Fluconazole has fungistatic activity. It is a aynthetic 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 South American blastomycosis.
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.
Clinical Context:
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. It is used to treat South American blastomycosis in Central America and South America primarily because of its low cost. It is not the drug of choice.
Patients with severe South American blastomycosis (paracoccidioidomycosis) may need to be hospitalized for intravenous antifungal medication and supportive care.
During and after treatment of South American blastomycosis (paracoccidioidomycosis) with antifungal medications, patients must be regularly evaluated to ensure an adequate response and a lack of 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 are considered to indicate a cure.
Superinfection with bacteria or other fungal pathogens is always a concern 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.
The destruction of mucous membranes can lead to perforation of the palate or nasal septum.
The destruction of the adrenal glands can cause Addison disease.
The severe fibrosis that accompanies healing often results in long-term sequelae. These sequelae may occur despite adequate treatment. Facial lesions heal with disfiguring scarring. Severe pulmonary fibrosis can occur and lead to chronic dyspnea and even cor pulmonale. Mucous membrane scarring can lead to buccal atresia, dysphonia, laryngeal stenosis, or tracheal stenosis.
Kendall M Egan, MD, Staff Dermatologist, Naval Medical Center San Diego
Disclosure: Nothing to disclose.
Specialty Editors
Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, Affiliate Associate Professor of Pediatrics and Pathology, University of Florida College of Medicine
Disclosure: Nothing to disclose.
David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD, Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York
Julie E Dixon, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Medical Association
Disclosure: Nothing to disclose.
Norman Levine,MD Private Practice, Tucson, AZ
Norman Levine is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Acknowledgments
The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of the Navy, Department of the Army, Department of Defense, or the U.S. Government.
Stickland GT, ed. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa: WB Saunders; 2000:559-61.
Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.
Crusted plaques over the central part of the face in a man with South American blastomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.
Crusted plaques over the central part of the face in a man with South American blastomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.
Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.
){kind=link}
){kind=link}