AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

South American blastomycosis is a serious, systemic mycotic infection caused by the thermally dimorphic fungus Paracoccidioides brasiliensis. The fungus is endemic to countries in Central America and South America, most notably Brazil, Argentina, Colombia, and Venezuela, in regions classified as subtropical mountain forests. Infection with P brasiliensis is usually subclinical; however, the fungus sometimes proliferates, causing severe disease.

Two general forms of the disease exist: the subacute juvenile form and the chronic adult form. The chronic adult form accounts for more than 90% of cases. The lungs, skin, mucous membranes, and lymph nodes most frequently are involved. Other internal organs sometimes are affected.

Pathophysiology

P brasiliensis is a thermally dimorphic fungus that grows as a mycelium in nature and as yeastlike cells in tissue. Although P brasiliensis has been cultured from the soil, its natural habitat is not well understood. The disease is believed to be initially acquired through the inhalation of the fungus, as with other dimorphic fungi. After the inhalation of conidia, the fungus transforms into yeast cells within the alveolar macrophages. In most patients who are immunocompetent, infection is subclinical, and fungal growth is halted. However, in some patients, after an incubation period of weeks to decades, the fungus reactivates and disseminates, causing granulomatous disease in multiple tissues. Most commonly, the lungs are affected, followed by the mucous membranes, skin, lymph nodes, and various internal organs.

Frequency

United States

The fungus is not endemic to the United States. A number of cases have been reported in patients who previously visited or resided in endemic areas.

International

South American blastomycosis is restricted to Central America and South America, with about 80% of cases occurring in Brazil. About 6-50% of people living in endemic regions have positive paracoccidioidin skin test results, which indicate prior infection. Antibodies to P brasiliensis have been detected in 27% of blood donors in Brazil. Of the 90 million people living in endemic areas, approximately 10 million are infected, although exact figures are difficult to obtain.

Mortality/Morbidity

• The mortality rate is high for both the chronic adult and subacute juvenile forms if untreated. With treatment, the mortality rate is 7-10% for children and 1-10% for adults.
• In patients with HIV, the mortality rate is 30-45%.
• 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 (ie, Addison disease) can develop.

Sex

• The chronic adult form affects men more frequently than women, with a ratio of about 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 extreme 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 subacute juvenile type.
• The subacute juvenile form affects both sexes equally.

Age

• Most patients are adult men aged 30-50 years.
• Children are affected in only 3-5% of cases.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

After the inhalation of conidia, the fungus transforms into yeastlike cells inside the alveolar macrophages. This transformation induces a nonspecific inflammatory response, which generally limits the disease at this point. Most patients have no signs or symptoms.

• Adult chronic
• • After a latency period of weeks to decades, some adults have a chronic progressive form of the disease. The skin, mucous membranes, lungs, and lymph nodes primarily are affected.
  • Constitutional symptoms include low-grade fever, malaise, and weight loss.
  • Mucous membrane symptoms include pain at ulceration sites. Oral lesions may lead to pain with eating or drinking. Laryngeal and pharyngeal lesions can cause dysphagia, hoarseness, or stridor.
  • Respiratory symptoms include cough; mucous production, which may be blood-tinged; and dyspnea. Symptoms due to involvement of other organ systems are sometimes seen, such as abdominal pain from gastrointestinal involvement or headache from central nervous system involvement.
• Juvenile subacute
• • After a brief latency period, some children have a subacute severe disseminated form of the disease. In children, the major target of South American blastomycosis is the reticuloendothelial system.
  • Symptoms include fever, asthenia, anorexia, malaise, weight loss, and diarrhea.
  • Mucous membrane and respiratory symptoms are unusual.
  • Most other symptoms are related to lymph node enlargement, suppuration, and sinus tract formation.

Physical

• Adult chronic
• • Mucous membranes: Approximately one half of patients with chronic disseminated disease seek medical attention because of mucocutaneous lesions. Oral, nasal, pharyngeal, and laryngeal lesions begin as papules or plaques, which ulcerate. The lesions typically have granulomatous, mulberrylike surfaces and most commonly occur on the lips, gingiva, palate, buccal mucosa, and tongue. Lesions progress over months and are painful. Gingival lesions cause the loss of teeth, which makes eating difficult. Lesions slowly enlarge and coalesce, increasing the difficulties. Conjunctivitis and ulcerative lesions of the perianal area occasionally occur.
  • Skin: Skin lesions, which occur most commonly on the face, are polymorphous. They may be papular, nodular, ulcerated, papillomatous, or even tuberous. They most often arise from the direct extension of mucous membrane lesions. Occasionally, hematogenous spread results in widely scattered lesions and subcutaneous abscesses. Lymph node breakdown can lead to cutaneous fistulae. Without treatment, lesions gradually enlarge.
  • Lymph nodes: Extensive lymphadenopathy develops. Numerous visceral and subcutaneous nodes may be involved through hematogenous and lymphatic spread. Cervical nodes are commonly affected. Nodes are hypertrophic, firm, and painful. They sometimes suppurate, forming sinus tracts 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, the lungs are the only organ system involved. The clinical picture often resembles that of tuberculosis. Chronic dyspnea, cough, and sputum production 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 causes mental status changes and seizures. Occasionally, adrenal insufficiency due to the destruction of the adrenal glands is observed. Intestinal ulcerations and osteomyelitis are other infrequent manifestations.
• Juvenile subacute
• • Mucous membranes: Mucosal involvement is rare, but mucosal ulcerations occasionally occur.
  • Skin: Subacute disease may be associated with an acneiform eruption or subcutaneous abscesses. Sometimes, scrofuloderma is produced as a result of suppuration of the underlying lymph nodes.
  • Lymph nodes: Lymphadenopathy is prominent. Nodes may enlarge to such a point that infection with P brasiliensis may be confused with leukemia or lymphoma. Lymph nodes often suppurate and form sinus tracts to the skin. Mesenteric adenopathy may lead to bowel obstruction.
  • Respiratory: Pneumonia sometimes occurs.
  • Other: Cachexia, hepatosplenomegaly, adrenal insufficiency, osteomyelitis, and gastrointestinal problems may also occur.

Causes

• The disease is caused by the inhalation of the fungus P braziliensis. Animal-to-human and human-to-human transmissions do not appear to occur. Direct inoculation of the skin or mucosal surfaces is rare.
• Rural workers, particularly woodcutters, are more frequently affected because of their increased contact with the soil.
• Alcohol and possibly tobacco smoking is associated with disseminated disease.
• South American blastomycosis has been identified as an AIDS-associated opportunistic infection. Patients with AIDS usually have a form of the disease that closely resembles the juvenile subacute type.
• Otherwise healthy patients who develop disseminated disease appear unable to mount a sufficient cellular immune response to the organism.

DIFFERENTIALS

Section 4 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Tuberculosis
Granulomatous candidosis
Histoplasmosis
Natural killer cell lymphoma
North American blastomycosis
Carcinomas
Lymphoma
Leukemia

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Direct examination
• • The diagnosis of South American blastomycosis often is made recognizing the fungus on wet preparations.
  • The microscopic examination of pus or superficial scrapings from mucosal lesions reveals thick-walled spherical yeast cells with multiple peripheral buds encircling a mother cell (ie, pilot's wheal or mariner's wheal).
  • This pilot's wheel configuration measures as long as 60 µm in diameter and is highly characteristic of P brasiliensis.
  • If microscopic examination does not reveal spores with multiple buds, fungal culturing may be necessary to differentiate the organism from other fungal pathogens.
• Culturing
• • Cultures on Sabouraud agar at room temperature yield the mold in 3-4 weeks.
  • P brasiliensis is a slowly growing mold with a white-to-tan aerial mycelium.
  • Subcultures on rich media at 37°C yield 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 South American blastomycosis.
• Serologic testing
• • Immunodiffusion and complement fixation are useful for the diagnosis of South American blastomycosis.
  • Results with both tests are positive in about 85-95% of patients with active disease, although cross-reactions with histoplasmosis can occur.
  • Complement fixation is quantitative and, therefore, is useful for following disease progression and response to therapy.
  • Recently, monoclonal antibodies to antigenic compounds of P brasiliensis (43-kd and 70-kd glycoproteins) have been developed. Using inhibition enzyme-linked immunosorbent assays, the sensitivity and specificity of these antibodies exceed 95%. These tests may prove useful for diagnosing South American blastomycosis in anergic or immunocompromised patients and for monitoring response to treatment.

Imaging Studies

• If clinically indicated, a chest radiograph should be obtained.
• • A chest radiograph often shows opaque bilateral lesions that are generally nodular but sometimes cavitary.
  • Lesions usually involve the perihilar and basilar portions of the lungs. This finding can help to differentiate South American blastomycosis from tuberculosis, which has a propensity to involve the upper lobes of the lungs.
• If clinically indicated, computed tomography or magnetic resonance imaging of the brain should be obtained to evaluate central nervous system involvement.

Other Tests

• If warranted, pulmonary function tests may reveal obstructive abnormalities, but the results are generally mild compared with the radiographic findings.

Procedures

• Lesional biopsies are helpful in diagnosis.

Histologic Findings

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. Tissue repair is seen as collagen fibrosis.

TREATMENT

Section 6 of 11  

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Medical Care

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

Surgical Care

• 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.

Consultations

• A pulmonologist or internal medicine specialist may be consulted, as warranted by the pulmonary symptoms or internal organ dysfunction.
• A consultation with an infectious disease specialist may be necessary if the diagnosis is uncertain.
• Rarely, consultation with a surgeon is needed.

MEDICATION

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Antifungal medications are the mainstay of treatment for South American blastomycosis. Most conditions respond well to these agents. Itraconazole, ketoconazole, fluconazole, amphotericin B, trimethoprim and sulfamethoxazole (TMP-SMZ), and sulfadiazine have all been successfully used to treat South American blastomycosis. Itraconazole and ketoconazole have become the drugs of choice in treatment; itraconazole is generally considered the superior of the 2.

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 are required. The percentage of patients who have a relapse after receiving sulfonamides is 20-30%, whereas with itraconazole it is 3.5-10%, and with ketoconazole it is 7-11%. Further, 3-5 years of sulfonamide therapy may be required, whereas 6-10 months and 6-12 months are recommended with itraconazole and ketoconazole, respectively.

Fluconazole is not as effective or well tolerated 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 (CSF) well.

Amphotericin B is used in patients with severe disease who cannot tolerate oral medications. It generally is given for 4-8 weeks and followed by sulfonamides for 2-3 years. Because of its high rate of adverse reactions and low patient tolerance, its use is reserved for the most ill patients. Its low cost is an advantage in Central America and South America. 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 remain the mainstays of treatment for South American blastomycosis because of their low cost.

Recent case reports have documented successful treatment with voriconazole and terbinafine.

Drug Category: Antifungals

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.

Drug Category: Antibiotics

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

FOLLOW-UP

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Further Inpatient Care

• Patients with severe disease who cannot tolerate oral medications must be admitted to the hospital for intravenous antifungal medication and supportive care.

Further Outpatient Care

• During and after treatment 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.

In/Out Patient Meds

• Antifungal medications, as described in Medication, are indicated.

Deterrence/Prevention

• No vaccine against P brasiliensis has been developed.
• No known control measures prevent South American blastomycosis.

Complications

• 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 occur despite adequate treatment.
• • Facial lesions heal with disfiguring facial 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.

Prognosis

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

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to consider the diagnosis in a patient who previously resided in or visited an endemic area

Special Concerns

• Pregnancy
• • South American blastomycosis is uncommon in women of childbearing age. However, in one large epidemiologic study in Brazil, 6 patients were pregnant during treatment. In one case, 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 South American blastomycosis 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, South American blastomycosis 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 TMP-SMZ for Pneumocystis pneumonia prophylaxis and ketoconazole for oropharyngeal candidiasis prophylaxis has aided in the reduction in disseminated P brasiliensis infections.
  • AIDS is primarily seen in urban areas, whereas South American blastomycosis is seen primarily in rural areas further 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.

MULTIMEDIA

Section 10 of 11  

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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
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Media type:  Photo

Media file 2:  Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Miscellaneous
• Multimedia
• References

• Benard G, Kavakama J, Mendes-Giannini MJ, et al. Contribution to the natural history of paracoccidioidomycosis: identification of the primary pulmonary infection in the severe acute form of the disease--a case report. Clin Infect Dis. Jan 1 2005;40(1):e1-4. [Medline].
• Blotta MH, Mamoni RL, Oliveira SJ, et al. Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases in the southeast region. Am J Trop Med Hyg. Sep 1999;61(3):390-4. [Medline].
• Corti M, Villafañe MF, Negroni R, Palmieri O. Disseminated paracoccidioidomycosis with peripleuritis in an AIDS patient. Rev Inst Med Trop Sao Paulo. Jan-Feb 2004;46(1):47-50. [Medline].
• Crissey JT, Lang H, Parish LC. Manual of Medical Mycology. Cambridge, Mass: Blackwell Sciences; 1995:. 128-34.
• Elder D, Elenitsas E, Jawarsky C, et al, eds. Lever's Histopathology of the Skin. 8th ed. Philadelphia, Pa: Lippincott-Raven; 1997:. 526, 532-3.
• Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens, and Practice. New York, NY: Churchill Livingstone; 2001:. 300-02.
• Hay RJ. Antifungal drugs used for systemic mycoses. Dermatol Clin. Jul 2003;21(3):577-87. [Medline].
• Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol. Dec 2005;53(6):931-51, quiz 952-4.
• Maluf ML, Pereira SR, Takahachi G, Svidzinski TI. [Prevalence of paracoccidioidomycosis infection determined by sorologic test in donors'' blood in the Northwest of ParanĂ¡, Brazil]. Rev Soc Bras Med Trop. Jan-Feb 2003;36(1):11-6. [Medline].
• Marques da Silva SH, Queiroz-Telles F, Colombo AL, et al. Monitoring gp43 antigenemia in Paracoccidioidomycosis patients during therapy. J Clin Microbiol. Jun 2004;42(6):2419-24. [Medline].
• Mayr A, Kirchmair M, Rainer J, et al. Chronic paracoccidioidomycosis in a female patient in Austria. Eur J Clin Microbiol Infect Dis. Dec 2004;23(12):916-9. [Medline].
• Ollague JM, de Zurita AM, Calero G. Paracoccidioidomycosis (South American blastomycosis) successfully treated with terbinafine: first case report. Br J Dermatol. Jul 2000;143(1):188-91. [Medline].
• Pereira RM, Tresoldi AT, da Silva MT, Bucaretchi F. Fatal disseminated paracoccidioidomycosis in a two-year-old child. Rev Inst Med Trop Sao Paulo. Jan-Feb 2004;46(1):37-9. [Medline].
• Richardson MD, Warnock DW, eds. Fungal Infection: Diagnosis and Management. 2nd ed. London: Bailliere Tindall; 1997:. 191-4.
• Sant''Anna GD, Mauri M, Arrarte JL, Camargo H Jr. Laryngeal manifestations of paracoccidioidomycosis (South American blastomycosis). Arch Otolaryngol Head Neck Surg. Dec 1999;125(12):1375-8. [Medline].
• Stickland GT, ed. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa: WB Saunders; 2000:. 559-61.
• Yasuda MA. Pharmacological management of paracoccidioidomycosis. Expert Opin Pharmacother. Mar 2005;6(3):385-97. [Medline].
• da Silva SH, Grosso Dde M, Lopes JD, et al. Detection of Paracoccidioides brasiliensis gp70 circulating antigen and follow-up of patients undergoing antimycotic therapy. J Clin Microbiol. Oct 2004;42(10):4480-6. [Medline].
• de Almeida SM, Queiroz-Telles F, Teive HA, et al. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. Feb 2004;48(2):193-8. [Medline].

Article Last Updated: Feb 1, 2007