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Penicilliosis
Penicilliosis and HIV
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Introduction
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Microbiology and Epidemiology
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Clinical Presentation
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Diagnosis
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Therapy and Prevention
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References
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Tables
Table 1.Clinical Features of Penicilliosis
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Related Resources
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Introduction
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Penicilliosis is an infection caused by Penicillium marneffei, a dimorphic fungus endemic to Southeast Asia and the southern part of China.(1) Rarely noted before the AIDS epidemic, P marneffei infections have become more prevalent in the endemic areas in conjunction with the AIDS epidemic.(2,3) Persons affected by penicilliosis usually have AIDS with low CD4 lymphocyte counts, typically <100 cells/µL. The average CD4 count at presentation is 63.5 cells/µL.(2,4) Patients with penicilliosis occasionally are seen outside endemic areas, but most have a history of travel to an endemic area.(5-8) The most common presentation is a disseminated infection manifested by fever, skin lesions, anemia, generalized lymphadenopathy, and hepatomegaly.(2) Localized infection such as pneumonia also has been reported.(7)

Patients with penicilliosis have a poor prognosis without treatment.(2) P marneffei demonstrates in vitro susceptibility to multiple antifungal agents including ketoconazole, itraconazole, miconazole, flucytosine, and amphotericin B.(9) Response rates of up to 97% have been reported with amphotericin B therapy for the first 2 weeks followed by 10 weeks of itraconazole.(4) Relapse occurs in the absence of prophylaxis in approximately 50% of patients after discontinuation of successful therapy.(10,11) Maintenance therapy with itraconazole is effective for prevention of relapse.(11)

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Microbiology and Epidemiology
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P marneffei appears in tissue as a unicellular yeastlike organism that reproduces by planate division.(12) The fungus is a mold at room temperature and it coverts to the yeast form if incubated at 37° C. This dimorphism is not found in other known members of the genus Penicillium. In the mycelial form on culture, the mold grows relatively fast, producing a grayish-white and downy or woolly colony in 2-3 days. The underside of the fungus appears either pink or red due to the production of a characteristic soluble red pigment that diffuses into the agar. Over time, the colony becomes more rugose while the aerial mycelia become pink. The color of the colony changes from white to light brown to light green after 10 days. The yeastlike cells are oval or cylindrical and are about 3-6 microns in length. Unlike the mold, the colonies of yeast do not produce a red pigment. The organism can be cultured from various clinical specimens including blood, bone marrow, skin, sputum, bronchoalveolar lavage fluid, and lymph nodes.

P marneffei is endemic to Southeast Asia and the southern part of China, where it has been isolated from 4 species of bamboo rats and from soil.(1,13,14) Infection seems to be more frequent in the rainy season.(15) Recent history of occupational or other exposure to a potential environmental reservoir of organisms in the soil has been shown to be the predominant risk factor for infection in susceptible persons.(16)

Infection rarely was documented before the AIDS epidemic. The first report of natural infection with P marneffei was in a person with Hodgkin lymphoma who had lived in Southeast Asia.(17) Only 8 cases of infection with P marneffei were reported between 1964 and 1983.(18) The prevalence of infection has increased substantially, especially in persons who are infected with HIV.(2) There were 92 cases diagnosed from 1987 to 1992 in Chiang Mai University Hospital, involving 86 patients who also were infected with HIV. Currently, this infection is the third most common opportunistic pathogen in patients with AIDS in Thailand, after tuberculosis and cryptococcosis, despite the fact that it is endemic only to the northern part of Thailand.(3)

Infections with P marneffei occasionally are seen outside the endemic area. Sporadic cases have been reported, all of which involved patients with a history connected to the endemic area.(5-8) The diagnosis should be considered in HIV-infected patients with fever, compatible clinical manifestations, and a history of travel to an endemic area.

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Clinical Presentation
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The clinical features of infection with P marneffei are shown in Table 1.(2) The most common presentation is fever and weight loss, occurring in more than 75% of patients. The average duration of symptoms prior to presentation is 4 weeks.(1,2) Other common manifestations include skin lesions, anemia, lymphadenopathy, and hepatomegaly with or without splenomegaly. Skin lesions are present in approximately two thirds of cases and can be varied in appearance. Generalized papular eruptions, central umbilicated papules resembling those of molluscum contagiosum, acnelike lesions and folliculitis all may occur. Skin lesions commonly occur on the face, trunk, and extremities. Pharyngeal and palatal lesions also can be seen.(19) Subcutaneous nodules occasionally can be seen.(2) Pulmonary symptoms (such as cough and dyspnea) occur in about 50% of cases. Chest radiographic abnormalities typically manifest as diffuse reticulonodular infiltrates, though 50% of cases have normal chest radiographs. Cavitary lesions also have been reported, particularly in patients with hemoptysis.(20) Laboratory findings include anemia, elevated transaminases (alanine and aspartate aminotransferase), and elevated alkaline phosphatase levels. Fungemia is observed in >50% of cases.

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Diagnosis
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Diagnosis usually is made by identification of fungi from clinical specimens. Biopsies of skin lesions, lymph nodes, and bone marrow demonstrate the presence of organisms on histopathology.(2) The fungi are spherical or oval in shape with basophilic intracellular or extracellular yeastlike appearance on Wright stain, often with clear central septation. The organism also can be identified on peripheral blood smear or bone marrow aspirate.(21) Blood cultures are positive frequently, while bone marrow culture is positive in nearly all cases.(2) The lysis centrifugation culture system may improve the yield of blood cultures. Histopathologic features include granulomatous, suppurative, or necrotizing inflammation.(22) Immunologic techniques to identify organisms on tissue samples are under evaluation with promising results.(23-30) A specific polymerase chain reaction (PCR) assay is under evaluation and might be useful as an alternative test for rapid diagnosis of P marneffei infection.(31-32)

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Therapy and Prevention
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Patients with penicilliosis have poor prognosis without treatment.(2) Even with treatment, mortality is approximately 20%. Treatment with amphotericin B with or without flucytosine, or itraconazole, is the treatment of choice.(10,33) P marneffei demonstrates in vitro susceptibility to many of the currently available antifungal agents, including ketoconazole, itraconazole, miconazole, flucytosine, and amphotericin B.(9,34) Fluconazole appears to be less active in vitro.(9) Clinical failure is more common in treatment with fluconazole (63.8%) compared with amphotericin B (22.8%) or itraconazole (25%).(9) Newer azoles (posaconazole, ravuconazole, and voriconazole) have demonstrated good in vitro activity against P marneffei.(35)

There are no randomized, controlled trials of the treatment of penicilliosis. One open-label study of amphotericin B 0.6 mg/kg/day intravenously for 2 weeks followed by 10 weeks of itraconazole 400 mg/day showed excellent results.(4) This regimen was effective in 97% of 74 HIV-infected patients treated. All patients had cleared fungemia by the end of their second week of treatment. Patients tolerated the regimen without any major adverse reactions.

After completing initial treatment, patients with P marneffei infection should receive secondary prophylaxis to prevent relapse of infection. A randomized controlled trial demonstrated that secondary prophylaxis with itraconazole 200 mg daily is effective.(11) None of the patients receiving itraconazole had a relapse, whereas 57% of those in the placebo group had a relapse within 1 year after completing initial treatment. Although this study was not powered to detect a survival difference, 15% of the patients who had a relapse died.

Primary prophylaxis can prevent the occurrence of penicilliosis. A randomized placebo-controlled study from Chiang Mai University suggests that primary prophylaxis with itraconazole 200 mg daily can prevent the occurrence of penicilliosis among patients with AIDS and CD4 counts <200 cells/µL.(36) Of 129 patients enrolled, penicilliosis occurred in only 1 case in the itraconazole arm compared with 11 cases in the placebo arm, a statistically significant difference (p = .008 in those who had CD4 counts <100 cells/µL). In addition, there were fewer cases of cryptococcosis and candidiasis in itraconazole arm, but no survival difference between arms was detected.

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References

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1.   Duong TA. Infection due to Penicillium marneffei, an emerging pathogen: review of 155 reported cases. Clin Infect Dis 1996; 23:125-30.
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2.   Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994; 344:110-3.
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3.  Supparatpinyo K, Sirisanthana T. New fungal infections in the Western Pacific. JAMA Southeast Asia 1994;10:Suppl 3:208-9.
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4.   Sirisanthana T, Supparatpinyo K, Perriens J, Nelson KE. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis 1998; 26:1107-10.
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5.   Sobottka I, Albrecht H, Mack D, Stellbrink HJ, van Lunzen J, Tintelnot K, Laufs R. Systemic Penicillium marneffei infection in a German AIDS patient. Eur J Clin Microbiol Infect Dis 1996; 15:256-9.
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6.   Remadi S, Lotfi C, Finci V, Ismail A, Rogiano D, Vassilakos P, Seemayer TA. Penicillium marneffei infection in patients infected with the human immunodeficiency virus. A report of two cases. Acta Cytol 1995; 39:798-802.
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7.   Sekhon AS, Stein L, Garg AK, Black WA, Glezos JD, Wong C. Pulmonary penicillosis marneffei: report of the first imported case in Canada. Mycopathologia 1994; 128:3-7.
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8.   Piehl MR, Kaplan RL, Haber MH. Disseminated penicilliosis in a patient with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1988; 112:1262-4.
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9.   Supparatpinyo K, Nelson KE, Merz WG, Breslin BJ, Cooper CR, Jr., Kamwan C, Sirisanthana T. Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens. Antimicrob Agents Chemother 1993; 37:2407-11.
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10.   Supparatpinyo K, Chiewchanvit S, Hirunsri P, Baosoung V, Uthammachai C, Chaimongkol B, Sirisanthana T. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992; 75:688-91.
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11.   Supparatpinyo K, Perriens J, Nelson KE, Sirisanthana T. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficiency virus. N Engl J Med 1998; 339:1739-43.
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12.  Sigler L, Kennedy MJ. Aspergillus, Fusarium, and Other Opportunistic Moniliaceous Fungi. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. Washington: American Society for Microbiology Press; 1999:1212-41.
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13.   Ajello L, Padhye AA, Sukroongreung S, Nilakul CH, Tantimavanic S. Occurrence of Penicillium marneffei infections among wild bamboo rats in Thailand. Mycopathologia 1995; 131:1-8.
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14.   Chariyalertsak S, Vanittanakom P, Nelson KE, Sirisanthana T, Vanittanakom N. Rhizomys sumatrensis and Cannomys badius, new natural animal hosts of Penicillium marneffei. J Med Vet Mycol 1996; 34:105-10.
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15.   Chariyalertsak S, Sirisanthana T, Supparatpinyo K, Nelson KE. Seasonal variation of disseminated Penicillium marneffei infections in northern Thailand: a clue to the reservoir? J Infect Dis 1996; 173:1490-3.
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16.   Chariyalertsak S, Sirisanthana T, Supparatpinyo K, Praparattanapan J, Nelson KE. Case-control study of risk factors for Penicillium marneffei infection in human immunodeficiency virus-infected patients in northern Thailand. Clin Infect Dis 1997; 24:1080-6.
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17.   DiSalvo AF, Fickling AM, Ajello L. Infection caused by Penicillium marneffei: description of first natural infection in man. Am J Clin Pathol 1973; 60:259-63.
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18.   Deng ZL, Connor DH. Progressive disseminated penicilliosis caused by Penicillium marneffei. Report of eight cases and differentiation of the causative organism from Histoplasma capsulatum. Am J Clin Pathol 1985; 84:323-7.
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19.   Wortman PD. Infection with Penicillium marneffei. Int J Dermatol 1996; 35:393-9.
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20.   Cheng NC, Wong WW, Fung CP, Liu CY. Unusual pulmonary manifestations of disseminated Penicillium marneffei infection in three AIDS patients. Med Mycol 1998; 36:429-32.
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21.   Supparatpinyo K, Sirisanthana T. Disseminated Penicillium marneffei infection diagnosed on examination of a peripheral blood smear of a patient with human immunodeficiency virus infection. Clin Infect Dis 1994; 18:246-7.
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22.   Deng Z, Ribas JL, Gibson DW, Connor DH. Infections caused by Penicillium marneffei in China and Southeast Asia: review of eighteen published cases and report of four more Chinese cases. Rev Infect Dis 1988; 10:640-52.
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23.   Imwidthaya P, Sekhon AS, Mastro TD, Garg AK, Ambrosie E. Usefulness of a microimmunodiffusion test for the detection of Penicillium marneffei antigenemia, antibodies, and exoantigens. Mycopathologia 1997; 138:51-5.
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24.   Kaufman L, Standard PG, Jalbert M, Kantipong P, Limpakarnjanarat K, Mastro TD. Diagnostic antigenemia tests for penicilliosis marneffei. J Clin Microbiol 1996; 34:2503-5.
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25.   Kaufman L, Standard PG, Anderson SA, Jalbert M, Swisher BL. Development of specific fluorescent-antibody test for tissue form of Penicillium marneffei. J Clin Microbiol 1995; 33:2136-8.
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26.   Yuen KY, Wong SS, Tsang DN, Chau PY. Serodiagnosis of Penicillium marneffei infection. Lancet 1994; 344:444-5.
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27.   Hamilton AJ. Serodiagnosis of histoplasmosis, paracoccidioidomycosis and penicilliosis marneffei; current status and future trends. Med Mycol 1998; 36:351-64.
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28.   Desakorn V, Smith MD, Walsh AL, Simpson AJ, Sahassananda D, Rajanuwong A, Wuthiekanun V, Howe P, Angus BJ, Suntharasamai P, White NJ. Diagnosis of Penicillium marneffei infection by quantitation of urinary antigen by using an enzyme immunoassay. J Clin Microbiol 1999; 37:117-21.
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29.   Chaiyaroj SC, Chawengkirttikul R, Sirisinha S, Watkins P, Srinoulprasert Y. Antigen detection assay for identification of Penicillium marneffei infection. J Clin Microbiol 2003; 41:432-4.
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30.   Panichakul T, Chawengkirttikul R, Chaiyaroj SC, Sirisinha S. Development of a monoclonal antibody-based enzyme-linked immunosorbent assay for the diagnosis of Penicillium marneffei infection. Am J Trop Med Hyg 2002; 67:443-7.
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31.   Prariyachatigul C, Chaiprasert A, Geenkajorn K, Kappe R, Chuchottaworn C, Termsetjaroen S, Srimuang S. Development and evaluation of a one-tube seminested PCR assay for the detection and identification of Penicillium marneffei. Mycoses 2003; 46:447-54.
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32.   Tsunemi Y, Takahashi T, Tamaki T. Penicillium marneffei infection diagnosed by polymerase chain reaction from the skin specimen. J Am Acad Dermatol 2003; 49:344-6.
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33.  Drouhet E. Penicilliosis due to Penicillium marneffei: A new emerging systemic mycosis in AIDS patients traveling or living in Southeast Asia. Review of 44 cases reported in HIV infected patients during the last 5 years compared to 44 cases of non AIDS patients reported over 20 years. J Mycol Med. 1993;4:195-224.
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34.   Imwidthaya P, Thipsuvan K, Chaiprasert A, Danchaivijitra S, Sutthent R, Jearanaisilavong J. Penicillium marneffei: types and drug susceptibility. Mycopathologia 2001; 149:109-15.
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35.   Pfaller MA, Messer SA, Hollis RJ, Jones RN. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother 2002; 46:1032-7.
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36.   Chariyalertsak S, Supparatpinyo K, Sirisanthana T, Nelson KE. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis 2002; 34:277-84.
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