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Infectious Diseases > MEDICAL TOPICS
Paracoccidioidomycosis
Article Last Updated: Sep 21, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Christina M Schofield, MD, Instructor of Medicine, Uniformed Services University of Health Sciences; Consulting Staff, Department of Infectious Disease, Wilford Hall Medical Center, Lackland Air Force Base
Christina M Schofield is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Women's Association, Infectious Diseases Society of America, and Phi Beta Kappa
Coauthor(s):
Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, Brooke Army Medical Center and Associate Professor, Department of Medicine, Uniformed Service University of Health Sciences;
Asgar A Boxwalla, MD, Staff Physician, Department of Internal Medicine, Division of Infectious Diseases, St John Detroit Riverview Hospital
Editors: Pranatharthi Haran Chandrasekar, MD, Director of Infectious Disease Fellowship, Professor, Department of Internal Medicine, Harper Hospital, Wayne State University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Author and Editor Disclosure
Synonyms and related keywords:
paracoccidioidomycosis, South American blastomycosis, Paracoccidioides brasiliensis, endemic mycosis, dimorphic fungal infection, Lutz-Splendore-Almeida disease
Background
Paracoccidioidomycosis is a chronic progressive systemic mycosis that predominantly affects men from forested tropical and subtropical areas of South and Central America. Pulmonary infection is the most common manifestation; however, following dissemination, infection frequently involves the mucous membranes, skin, and lymph nodes. Other names include South American blastomycosis and Lutz-Splendore-Almeida disease.
Pathophysiology
The causative agent is a thermally dimorphic fungus, Paracoccidioides brasiliensis, which is isolated from the soil. Naturally acquired animal infection has been demonstrated only in armadillos. Bats and saguis may serve as reservoirs. The lungs are the primary site of infection, which occurs when conidia or mycelial fragments are inhaled. The organism then disseminates to other organs through the venous and lymphatic systems. Direct inoculation of the skin or oral mucous membranes is not common but may result from the use of twigs to clean teeth, which is practiced in rural Brazil. The intestinal mucosa can also serve as a site of direct inoculation if the fungus is ingested. Person-to-person transmission does not occur. Cellular immunity is the key defense mechanism in an immunocompetent host.
Frequency
United States
Rare cases are reported from North America; however, these patients had previously resided in endemic countries.
International
Paracoccidioidomycosis is restricted geographically to South and Central America, from Mexico (23° N) to Argentina (34° S), with the exception of Chile, Surinam, the Guyana, Nicaragua, Belize and most of the Caribbean Islands. The highest incidence is in the southeast province of Brazil, with an estimated annual incidence of 1-3 cases per 10,000 inhabitants. This is followed by Colombia, Venezuela, Ecuador, and Argentina. Within endemic regions, the disease is restricted ecologically 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 rainfall between 100 and 400 cm/year.
Mortality/Morbidity
- The mortality rate is high (16-25%) if untreated.
- The mortality rate in Brazil is estimated at 1.4 per 1 million inhabitants.
Sex
Men, especially farmers and hunters, are more commonly affected than women, with a mean male-to-female ratio of 15:1. Some of this unequal distribution is attributed to exposure; however, estrogens may have a role in inhibitory action on the conidia or mycelium-to-yeast transition of the organism.
Age
Paracoccidioidomycosis is rare in children and teenagers. Most patients are aged 30 years or older.
History
Most initial infections are subclinical. In younger patients, the disorder is subacute and carries a more severe prognosis; in adults, the course of disease is long term and the outcome is better with appropriate therapy. As demonstrated by patients who have developed symptoms 30 or more years after exposure, the period of latency can be long.
- Chronic adult form
- The chronic adult form is seen in 80-90% of cases and represents endogenous reactivation years after initial contact with the fungus.
- Primary lung infection: Productive cough, dyspnea, malaise, fever, and weight loss are common symptoms. Chronic pulmonary sequelae are seen in one third of patients and can include pulmonary fibrosis, bullae, and emphysematous changes that can contribute to pulmonary hypertension and cor pulmonale in 5% of cases.
- Mucous membrane involvement is seen in 50% of patients, with acute pulmonary infection resulting in dysphagia, dysphonia, and perioral granulomatous plaques. Gingival involvement may lead to tooth loss.
- Oral lesions can be associated with nasal and pharyngeal ulcers (Aguiar-Pupo stomatitis) and can be characterized by associated mandibular or cervical lymph node enlargement.
- Cutaneous involvement due to hematologic dissemination from the lungs is seen in 25% of cases. Rarely, these lesions can result from direct inoculation. Crusted papules, ulcers, nodules, plaques, and verrucous lesions are typical.
- Lymphadenopathy is also common in the cervical region, but all lymph node chains can be involved.
- Other sites of involvement include the following:
- Adrenal glands are affected in 48% of cases and can result in adrenal insufficiency in 15% of patients and addisonian crisis in 5-9% of patients.
- Long bones such as ribs, humeri, and clavicles can be involved.
- Mesenteric lymph node involvement can lead to bowel obstruction.
- Central nervous system involvement results in a meningoencephalitis as part of a disseminated syndrome in 10-25% of patients.
- In addition, disease rarely presents as an isolated meningitis or spinal cord lesion.
- Acute or subacute juvenile form
- Reticuloendothelial system involvement predominates with lymphadenopathy and hepatosplenomegaly.
- Systemic symptoms such as fever, weight loss, and malaise are present in most patients.
- Multiple skin lesions may be present.
Physical
Because diagnosis usually is delayed, patients are typically malnourished and anemic at presentation.
- Lungs
- Auscultatory findings are minimal in comparison with the radiologic abnormalities.
- In patients with chronic disease, the signs of right-sided heart failure (cor pulmonale) may be present (eg, jugular venous distension, hepatomegaly, dependent edema).
- Mucosal lesions
- Lesions are infiltrative, ulcerated, and commonly involve the mouth, lips, gingiva, tongue, and palate.
- Less commonly, these lesions can involve the nose, larynx, and pharynx.
- Ulcerated lesions are mulberry-like, and cicatricial scarring accompanies healing.
- Skin
- Lesions can be crusted papules, ulcers, nodules, plaques, or verrucous lesions.
- Lesions infiltrate the subcutaneous tissues.
- Lymphadenopathy
- Lymphadenopathy presents as localized swelling in the cervical axillary region.
- Mesenteric lymph node enlargement rarely can present as an abdominal mass.
- Draining fistulas may form.
- Adrenal involvement can present with features of addisonian syndrome.
Causes
Risk factors for disease include the following:
- Agricultural work (especially the coffee growers in Brazil)
- Young and middle-aged men who work outdoors as farmers or hunters (at great risk for chronic disease)
- Smoking
- Alcoholism
- Immunocompromising conditions (eg, AIDS) (In a study by Paniago et al, the incidence of paracoccidioidomycosis in patients with HIV/AIDS was 1.5%, which was higher than in the general population [0.02%]. Patients with AIDS are more likely to develop hematogenous dissemination and multiple organ involvement.)
Histoplasmosis
Leishmaniasis
Leprosy
Lymphoma, Non-Hodgkin
Syphilis
Tuberculosis
Lab Studies
- Microbiological
- Wet mount of sputum with 30% potassium hydroxide (KOH): Positive results are diagnostic in 93% of patients and consist of a demonstration of large, multiple budding yeasts (blastoconidia). These yeasts are unique in that one large mother cell produces multiple blastoconidia (daughter cells) that arise from multiple sites. This appearance has been described as resembling a "Mickey Mouse head" or a "pilot wheel" and helps differentiate this yeast from Blastomyces dermatitidis and all other yeasts.
- Biopsy specimens: Gomori methenamine silver (GMS) stain of specimens reveal yeast cells that range from 2-30 µm in diameter. Granuloma formation is typical in the adult form, while tissue reactions are diffuse in the juvenile form.
- Culture: The organism can be recovered at 37°C on Sabouraud dextrose agar. Cultures may require 20-30 days for growth.
- Serologic diagnosis (not available outside endemic areas)
- Immunodiffusion: This test reveals any circulating P brasiliensis antibodies. The sensitivity and specificity depend on the antigens used but are generally quoted in the 65-100% range. Early tests revealed antibodies to gp43, the main antigenic determinate of P brasiliensis, but the cross-reaction with histoplasmosis and Lobo disease (lobomycosis) is significant. Newer tests that detect Ag7 (antigen found after 7 d of growth) have improved sensitivity and specificity to 84% and 99%, respectively. This test can be used to monitor patient response to therapy and to detect recurrences.
- Complement fixation test: This test is useful but technically cumbersome. The test has a quantitative nature that allows evaluation of patient response to treatment but may cross-react with Histoplasma capsulatum antigens.
- Counter immunoelectrophoresis: This test has similar sensitivity and specificity as immunodiffusion. This 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]) 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 Lobo disease.
- Immunoblotting (eg, Western blot): This test detects circulating antibodies to gp43 in the serum in 100% of patients and to gp70 in 96% of patients.
- Skin testing is not reliable for diagnosis in endemic areas.
- In CNS disease, CSF studies are nonspecific and mycological examination findings are usually negative.
Imaging Studies
- Chest radiograph
- In a patient with active disease, this study reveals interstitial infiltrates in 64% of cases or mixed lesions with linear and nodular infiltrates. Lesions are frequently bilateral and symmetric.
- Most changes occur in the central and basal portions of the lungs; the apices usually are 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.
- In CNS disease, features on CT scan and MRI are nonspecific and similar to those seen in other granulomatous diseases.
Medical Care
- Supportive care
- Correct patient anemia.
- Improve patient diet.
- Ensure patient receives rest.
- Antifungal treatment
- Triazoles (itraconazole, fluconazole): Itraconazole is considered the drug of choice for paracoccidioidomycosis and is effective in 95% of patients. The dose required for itraconazole is 100-200 mg/day for a mean period of 6 months based on clinical response and mycology laboratory data. Itraconazole is considered superior to ketoconazole because of shorter treatment course, lower toxicity profile, and lower relapse rate (3-5%). Fluconazole can be used for CNS disease, as neither ketoconazole nor itraconazole effectively penetrates the blood-brain barrier; however, high doses (up to 600 mg/d) are required. Relapses are more common with fluconazole. Voriconazole, a newer 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.
- Imidazole (ketoconazole): This is also an effective agent, 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, may cause hepatic dysfunction and sex hormone alterations, and carries many drug-drug interactions.
- Sulfonamides (sulfadiazine, sulfamethoxypyridazine, sulfadimethoxine): 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 also a 30% relapse rate.
- Amphotericin B: Reserve this drug for severe cases 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 azole is subsequently required. This drug is available only for intravenous administration and its use is limited because of associated toxicities. The associated rate of improvement and relapse rate are similar to those of sulfonamide.
- A randomized controlled trial by Shikanai-Yasuda et al studied 42 patients with paracoccidioidomycosis randomized to receive itraconazole, ketoconazole, or sulfadiazine for 4-6 months. The clinical and serologic response was inadequate in 41 patients, so the authors were unable to show superiority of any one regimen.
Consultations
- Consult a dermatologist for skin biopsy.
- Consult an infectious disease specialist for a difficult diagnosis, especially in nonendemic areas, and for patients requiring long-term treatment with potentially toxic medications (eg, amphotericin B).
The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.
Drug Category: Antifungal agents
| Drug Name | Itraconazole (Sporanox) |
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| Description | Preferred over the previously used agent ketoconazole because it lacks the hepatic and endocrine toxicity observed with the latter and also is efficacious at lower doses. Synthetic triazole is an antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. |
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| Adult Dose | 100 mg PO qd for 6 mo |
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| Pediatric Dose | Not established; 100 mg PO qd suggested dose for fungal infections |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death
May increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered) |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in hepatic insufficiency |
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| Drug Name | Ketoconazole (Nizoral) |
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| Description | Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death. |
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| Adult Dose | 200-400 mg/d PO for 6 to 18 mo |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; fungal meningitis |
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| Interactions | Isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels; decreases metabolism of repaglinide, thus increasing serum levels and effects |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (side effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2-blockers at least 2 h after taking ketoconazole |
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| Drug Name | Sulfadiazine (Microsulfon) |
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| Description | Therapy with these agents is long term (3-5 y) and is associated with a high relapse rate of 20-25%. This condition is the only mycosis amenable to treatment with sulfa drugs. |
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| Adult Dose | Loading dose: 4 g PO
Maintenance dose: 4 g/d PO in 3-6 divided doses; not to exceed 6 g/d |
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| Pediatric Dose | <2 months: Not recommended
>2 months loading dose: 75 mg/kg or 2 g/m2 PO; not to exceed 6 g/d
>2 months maintenance dose: 150 mg/kg/d or 4 g/m2/d PO in 4-6 divided doses; not to exceed 6 g/d |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Increases effect of oral anticoagulants and oral hypoglycemic agents; sulfadiazine effects are decreased when administered concurrently with PABA or PABA metabolites of drugs such as proparacaine, tetracaine, sunscreens, and procaine |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in impaired renal function, hepatic function, or G-6-PD deficiency; adjust dose in renal insufficiency; can cause bone marrow suppression |
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| Drug Name | Amphotericin B, conventional (Amphocin, Fungizone, Ambisome) |
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| Description | Produced from a strain of Streptomyces nodosus. Antifungal activity of amphotericin B results from ability to insert itself into 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; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, 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. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.
Liposomal amphotericin is a novel lipid formulation of amphotericin B that delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Not curative by itself. All patients treated with this require maintenance treatment with sulfonamide or an azole. Improvement occurs in 65-70% of patients treated with this agent. |
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| Adult Dose | 0.5-0.7 mg/kg/d IV infusion over 4 h
Alternatively, 3-5 mg/kg/d IV liposomal amphotericin B over approximately 120 min
A total of 1200-3000 mg (conventional formulation amphotericin B) may be required |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Monitor renal function, serum electrolytes such as magnesium and potassium, liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock |
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Complications
- General complications include malnourishment and anemia.
- Pulmonary complications include hemoptysis, pulmonary fibrosis, and chronic cor pulmonale.
- Endocrine complications include Addison syndrome.
Prognosis
- The juvenile form of this mycosis has a poor prognosis; however, the adult form is chronic, with a better prognosis.
- The advent of the newer azole agents has provided a significant and favorable impact on disease prognosis.
Medical/Legal Pitfalls
- Failure to diagnose this disease in a timely manner in nonendemic areas because of the lack of familiarity of the disease and its various forms of presentation
- Failure to inquire about patient's previous country of residence, even if in the remote past, which can be an important clue to diagnosis. Some patients develop overt disease 30 or more years after leaving the endemic regions.
Special Concerns
- Coexistence with tuberculosis in 15-20% of cases has been reported.
| Media file 1:
Paracoccidioidomycosis. Approximate distribution of the disease in North, Central, and South America, based on case reports. |
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| Media file 2:
Paracoccidioidomycosis. Granulomatous lesion involving the nose; note the resemblance with cutaneous leishmaniasis. |
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Media type: Photo
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| Media file 3:
Paracoccidioidomycosis. Potassium hydroxide (KOH) preparation from pus; note the multiple budding and variation in cell size. |
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Paracoccidioidomycosis excerpt Article Last Updated: Sep 21, 2006
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