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Paracoccidioidomycosis
Paracoccidioidomycosis and HIV
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Introduction
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Clinical Presentation in HIV-Infected Individuals
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Diagnosis
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Treatment
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References
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Related Resources
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Introduction
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Paracoccidioidomycosis is a systemic fungal infection caused by Paracoccidioides brasiliensis, endemic in Latin America. Similar to blastomycosis, paracoccidioidomycosis is not an AIDS-defining illness, and there are only 79 cases in HIV-infected individuals reported in the literature.(1) Like other systemic mycoses, infection begins with inhalation of spores, leading to localized pulmonary infection and frequently dissemination to the skin, mucous membranes, and reticuloendothelial system. Diagnosis is dependent on identification of the fungus on histology or by culture. The treatment of choice remains amphotericin B, although azole therapy, particularly itraconazole 200 mg twice daily, may be effective and is frequently used as first-line treatment, especially in milder forms of disease. Terbinafine may be an alternative to itraconazole.(2,3) Sulfa-trimethoprim may have some activity but is associated with high relapse rates.

Paracoccidioidomycosis is restricted geographically to certain areas of Latin America. The disease is rare in children and adolescents. The chronic form preferentially affects men compared to women (ratio 15:1), which is intriguing given the fact that skin test surveys demonstrate similar exposure rates between the sexes.(4) Risk factors for development of disease include occupational exposure and alcoholism. It is unclear whether infection among HIV-infected individuals is due to new exposure or reactivation of latent disease. As with other systemic mycoses, disease most commonly occurs in HIV-infected persons with CD4 counts less than 200 cells/µL.

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Clinical Presentation in HIV-Infected Individuals
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HIV-related cases of paracoccidioidomycosis published in the literature through 1999 have been reviewed.(1) Partial clinical and epidemiologic data was available for 73 cases: 56 men and 17 women (ratio 3.3:1). The median age was 33.5 years (range 15-62). Coinfection with a second opportunistic infection, predominantly oral candidiasis or tuberculosis, occurred in 37%. Seventy-seven percent of the patients had disseminated disease characterized as lymphadenopathy (73%), hepatomegaly (43%), splenomegaly (29%), and osteoarticular lesions (18%). Skin involvement was much higher (61%) than that previously reported in the HIV-seronegative population (10-15%). The lesions were described as ulcerative papular lesions with occasional necrotic centers. Biopsies of these lesions were positive for P brasiliensis by either histology or culture. Involvement of the lung was noted in 55% of cases with 74% of chest radiographs demonstrating a diffuse interstitial pattern. Oral cavity involvement was noted in 32%.

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Diagnosis
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Skin tests and serologic markers are useful epidemiologic tools but are of inadequate sensitivity and specificity to be diagnostic. In the review of HIV-associated cases of paracoccidioidomycosis, only 57% of those who had serologic tests tested positive.(1) PCR and monoclonal antibodies as diagnostic tools are under investigation and appear promising.(5,6) Currently, diagnosis depends on direct examination of tissue or the isolation of P brasiliensis in culture.

Microscopy of tissue sections and cultures containing P brasiliensis, reveals oval to round 4- to 40-µm yeast cells that reproduce by budding. The characteristic "pilot's wheel" appearance, consisting of numerous small buds surrounding and connecting by cytoplasmic bridges to a mother cell, is diagnostic. Macroscopically, the colony initially appears yeastlike at room temperature and then develops hyphal projections, eventually becoming a fluffy white mold with a brownish base. The yeast form grows as a soft, cream-colored colony and develops a cerebriform texture at 37°C.(4)

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Treatment
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As there are no randomized, comparative trials of treatment for paracoccidioidomycosis in HIV-infected subjects, the optimal therapy is unknown. Amphotericin B remains the drug of choice for severe or life-threatening disease and should be administered up to a cumulative dose of 1.5-2.5 g followed by either sulfa or azole maintenance therapy. Overall mortality on therapy is about 25%. Sulfadiazine 4-6 g daily may be given for mild to moderate forms of disease for weeks to months, followed by a lower maintenance dose (usually half the initial dose) for 3-5 years to prevent relapse. HIV-infected individuals should remain on lifelong maintenance therapy. Sulfa-trimethoprim may be substituted for sulfadiazine.

Ketoconazole 200-400 mg daily or itraconazole 200 mg twice daily may be used as an alternative, as both initial and life-long maintenance therapy. In a comparative trial of 22 patients randomized to ketoconazole and 32 patients randomized to amphotericin B plus sulfonamides, there was a trend toward clinical superiority in the ketoconazole arm.(7) HIV status of these patients is unknown, as the trial was performed in the early 1980s. In a small, randomized trial of 42 patients comparing itraconazole, ketoconazole, and sulfadiazine, there was no difference in clinical response among the three arms.(8) A small animal study suggests that fluconazole may also be effective,(9) however the US national guidelines recommend against fluconazole use due to its high failure rate.(10) In the absence of data, most experts recommend that HIV-infected patients with paracoccidioidomycosis should be treated with amphotericin B followed by maintenance with either a sulfa or itraconazole 100-200 mg daily or ketoconazole 200-400 mg daily.(10) Based on tolerability and efficacy reported in other systemic mycoses, itraconazole has become the preferred agent. Terbinafine 250 mg twice daily may also have a role, but further studies are needed to determine its efficacy.(2,3) Similarly, the role of newer agents such as voriconazole, lipid preparations of amphotericin B, and echinocandins is unknown.

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References

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1.   Benard G, Duarte AJ. Paracoccidioidomycosis: a model for evaluation of the effects of human immunodeficiency virus infection on the natural history of endemic tropical diseases. Clin Infect Dis. 2000 Oct;31(4):1032-9.
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2.   Hahn RC, Fontes CJ, Batista RD, Hamdan JS. In vitro comparison of activities of terbinafine and itraconazole against Paracoccidioides brasiliensis. J Clin Microbiol. 2002 Aug;40(8):2828-31.
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3.   Ollague JM, de Zurita AM, Calero G. Paracoccidioidomycosis (South American blastomycosis) successfully treated with terbinafine: first case report. Br J Dermatol. 2000 Jul;143(1):188-91.
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4.  Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 5th edition. Churchill Livingston, 2000. Section G. Mycoses. Paracoccidioides brasiliensis by Restrepo AM.
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5.   Gomes GM, Cisalpino PS, Taborda CP, de Camargo ZP. PCR for diagnosis of paracoccidioidomycosis. J Clin Microbiol. 2000 Sep;38(9):3478-80.
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6.   Gomez BL, Figueroa JI, Hamilton AJ, Ortiz B, Robledo MA, Hay RJ, Restrepo A. Use of monoclonal antibodies in diagnosis of paracoccidioidomycosis: new strategies for detection of circulating antigens. J Clin Microbiol. 1997 Dec;35(12):3278-83.
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7.   Marques SA, Dillon NL, Franco MF, Habermann MC, Lastoria JC, Stolf HO, Marcondes J, Grizzo W, Silva NC, Cavariani MR, et al. Paracoccidioidomycosis: a comparative study of the evolutionary serologic, clinical and radiologic results for patients treated with ketoconazole or amphotericin B plus sulfonamides. Mycopathologia. 1985 Jan;89(1):19-23.
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8.   Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GM, Hoo S, Vaccari EH, Gryschek RC, Segurado AA, Barone AA, Andrade DR. Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med Mycol. 2002 Aug;40(4):411-7.
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9.   Martinez R, Malta MH, Verceze AV, Arantes MR. Comparative efficacy of fluconazole and amphotericin B in the parenteral treatment of experimental paracoccidioidomycosis in the rat. Mycopathologia. 1999;146(3):131-4.
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10.   Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK; CDC; National Institutes of Health; Infectious Diseases Society of America. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004 Dec 17;53(RR-15):1-112.
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