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Penicilliosis marneffei
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Epidemiology

Penicilliosis marneffei (penicilliosis) is caused by the dimorphic fungus Penicillium marneffei, which is endemic in Southeast Asia (especially Northern Thailand) and southern China (1257Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in Southeast Asia. Lancet 1994;344:110-3., 1258Clezy K, Sirisanthana T, Sirisanthana V, Brew B, Cooper DA. Late manifestations of HIV in Asia and the Pacific. AIDS 1994;8(Suppl 2):35-43., 1259Kantipong P, Panich V, Pongsurachet V, Watt G. Hepatic penicilliosis in patients without skin lesions. Clin Infect Dis 1998;26:1215-7.). More recently, 50 indigenous cases of penicilliosis occurred in Manipur State, India, a new endemic area of this fungus (1260Singh PN, Ranjana K, Singh YI, et al. Indigenous disseminated Penicillium marneffei infection in the state of Manipur, India: report of four autochthonous cases. J Clin Microbiol 1999;37:2699-702., 1261Ranjana KH, Priyokumar K, Singh TJ, et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India. J Infect Dis 2002;45:268-71.). International travel requires increased awareness and recogntion of penicilliosis and its treatment.

Before the antiretroviral treatment era, penicilliosis was the presenting AIDS-defining illness in 6.8% of HIV-infected patients from the northern provinces of Thailand but less frequently elsewhere (1262Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994-1998: regional variation and temporal trends. Clin Infect Dis 2001;32:955-62.). The majority of cases of penicilliosis are observed in patients who have CD4+ counts of <100 cells/µL (1263Chariyalertsak 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.). The infection is associated with a high mortality rate if timely treatment with appropriate antifungal drugs is not administered (1264Supparatpinyo K, Nelson KE, Merz WG, et al. 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.).

Clinical Manifestations

The common clinical manifestations include fever, anemia, weight loss, and generalized skin papules with central umbilication resembling molluscum contagiosum (1257Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in Southeast Asia. Lancet 1994;344:110-3.). Cutaneous penicilliosis lesions commonly appear on the face, ears, extremities, and occasionally the genitalia. Involvement of other organs such as bone marrow, lymph node, lung, liver, and intestine have been reported. Patients with hepatic penicilliosis have fever, abdominal pain, hepatomegaly, and a marked increase in serum alkaline phosphatase levels (1259Kantipong P, Panich V, Pongsurachet V, Watt G. Hepatic penicilliosis in patients without skin lesions. Clin Infect Dis 1998;26:1215-7.).

Diagnosis

The definitive diagnosis of penicilliosis is based on isolation of organisms from blood culture or other clinical specimens or by histopathologic demonstration of organisms in biopsy material. Fungal cultures at 25°C (77°F) demonstrate characteristic features that include a flat green surface and underlying deep red coloring. An early presumptive diagnosis can be made several days before the results of fungal cultures are available by microscopic examination of the Wright-stained samples of skin scrapings, bone marrow aspirate, or lymph-node biopsy specimens. Many intracellular and extracellular basophilic, spherical, oval, and elliptical yeast-like organisms can be seen, some with clear central septation, which is a characteristic feature of P. marneffei (1257Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in Southeast Asia. Lancet 1994;344:110-3.). In some patients, the fungus can be identified by microscopic examination of the Wright's-stained peripheral blood smear (1265Supparatpinyo 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.).

Preventing Exposure

Available information does not support specific recommendations regarding exposure avoidance. However, patients with advanced HIV disease should avoid visiting the disease-endemic areas (BIII).

Preventing Disease

Not applicable to residents of the United States.

Treatment of Disease

P. marneffei is highly susceptible to miconazole, itraconazole, ketoconazole, and 5-flucytosine. Amphotericin B has intermediate antifungal activity, whereas fluconazole is the least active (1264Supparatpinyo K, Nelson KE, Merz WG, et al. 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.). The recommended treatment is amphotericin B in a dose of 0.6 mg/kg body weight/day administered intravenously for 2 weeks, followed by oral itraconazole in a dose of 400 mg/day for a subsequent duration of 10 weeks (AII) (1266Sirisanthana 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.). Patients with mild disease can be initially treated with oral itraconazole 400 mg/day for 8 weeks (BII) (1267Supparatpinyo K, Chiewchanvit S, Hirunsri P, et al. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992;75:688-91.), followed by 200 mg/day for prevention of recurrence. Itraconazole capsule is better absorbed when it is taken with or immediately after a meal. Itraconazole oral solution could be taken on an empty stomach. ART should be administered in accordance with standards of care in the community; consideration should be given to simultaneous administration of treatment for penicilliosis and initiation of ART to improve outcome (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte distur bances. Preinfusion administration of 500 mL of normal saline appears to reduce the risk for nephrotoxicity during treatment. Infusion-related adverse reactions might be ameliorated by pretreatment with acetaminophen and diphenhydramine; in rare cases, glucocorticosteroids administered approximately 30 minutes before the infusion might be required (CIII).

Because absorption of itraconazole can be erratic, serum itraconazole levels should be obtained once in all patients to ensure adequate absorption (AIII). The serum concentration should be >1 µg/mL, ideally drawn for reasons of consistency as a trough level after at least 7 days on the current regimen. Itraconazole solution is recommended over the capsule formulation because absorption is improved, but this has not been studied specifically in HIV-infected patients.

The immune restoration inflammatory syndrome has been reported uncommonly in patients with penicilliosis (1268Manosuthi W, Chaovavanich A, Tansuphaswadikul S, et al. Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting. J Infect 2007;55:464-9., 1269Gupta S, Mathur P, Maskey D, Wig N, Singh S. Immune Restoration Syndrome with disseminated Penicillium marneffei and Cytomegalovirus co-infections in an AIDS patient. AIDS Res Ther 2007;4:21.). It usually occurs within a few weeks or months after starting ART, suggesting a possibility of immune reconstitution unmasking active disease. ART should not be withheld because of concern for the possible development of IRIS (AIII). In patients with severely symptomatic IRIS, short-course glucocorticosteroids are recommended by certain specialists (BIII). Delaying the initiation of potent ART until the end of the first 2 weeks of induction therapy for penicilliosis might be prudent (CIII).

Management of Treatment Failure

Alternative treatment options for penicilliosis are not established. A small case series reported good outcomes with voriconazole (1270Supparatpinyo K, Schlamm HT. Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. Am J Trop Med Hyg 2007;77:350-3.). For those whose initial therapy has failed, the approach to treatment should consist of reinitiating parenteral amphotericin B followed by another course of oral itraconazole, coupled with optimizing ART, addressing obstacles to adherence, avoiding adverse drug interactions, and ensuring that adequate absorption and serum concentrations of itraconazole are achieved (AIII).

Preventing Recurrence

A study from Chiang Mai University documented that approximately 50% of patients had relapse of penicilliosis marneffei within 6 months after discontinuation of antifungal therapy (1267Supparatpinyo K, Chiewchanvit S, Hirunsri P, et al. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992;75:688-91., 1271Supparatpinyo 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.). A double-blind, placebo-controlled study from Chiang Mai, Thailand, demonstrated that oral itraconazole 200 mg daily for secondary prophylaxis in AIDS patients reduced the relapse rate of penicilliosis marneffei from 57% to 0% (p<0.001) (1271Supparatpinyo 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.). All patients who successfully complete treatment for penicilliosis should be administered secondary prophylaxis (chronic maintenance therapy) with oral itraconazole in a dose of 200 mg/day (AI).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

No randomized controlled study exists that could demonstrate the safety of discontinuation of secondary prophylaxis for penicilliosis. However, an open-label, historical-controlled trial from Chiang Mai University Hospital indicated that no relapse of penicilliosis and invasive fungal infections occurred after discontinuation of itraconazole in patients receiving ART and CD4+ cell count >100 cells/µL (1272Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007;21:365-7.). Therefore, discontinuing secondary prophylaxis for penicilliosis is recommended for AIDS patients who receive combination ART and have CD4+ count >100 cells/µL for ≥6 months (BII). Secondary prophylaxis should be reintroduced if the CD4+ count decreases to <100 cells/µL (AIII) or if penicilliosis recurs at a CD4+ count of >100 cells/µL (CIII).

Special Considerations During Pregnancy

The diagnosis and treatment of penicilliosis during pregnancy are similar to those in nonpregnant women with the following considerations regarding antifungal use in pregnancy. Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII) (See mucocutaneous candidiasis). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

TABLE 2. Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Penicilliosis
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Acute infection in severely ill patients
transparent gifgrey bulletAmphotericin B deoxycholate 0.6 mg/kg/day IV for 2 weeks; followed by itraconazole 400 mg PO daily for 10 weeks (AII)
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Mild disease
transparent gifgrey bulletItraconazole 400 mg PO daily for 8 weeks (BII)
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Chronic maintenance therapy (secondary prophylaxis)
transparent gifgrey bulletItraconazole 200 mg PO daily (AI)
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ART should be administered according to standard of care in the community; consideration should be given to simultaneously initiating ART and treatment for penicilliosis (CIII)

References

1257. Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in Southeast Asia. Lancet 1994;344:110-3.
1258. Clezy K, Sirisanthana T, Sirisanthana V, Brew B, Cooper DA. Late manifestations of HIV in Asia and the Pacific. AIDS 1994;8(Suppl 2):35-43.
1259. Kantipong P, Panich V, Pongsurachet V, Watt G. Hepatic penicilliosis in patients without skin lesions. Clin Infect Dis 1998;26:1215-7.
1260. Singh PN, Ranjana K, Singh YI, et al. Indigenous disseminated Penicillium marneffei infection in the state of Manipur, India: report of four autochthonous cases. J Clin Microbiol 1999;37:2699-702.
1261. Ranjana KH, Priyokumar K, Singh TJ, et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India. J Infect Dis 2002;45:268-71.
1262. Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994-1998: regional variation and temporal trends. Clin Infect Dis 2001;32:955-62.
1263. 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.
1264. Supparatpinyo K, Nelson KE, Merz WG, et al. 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.
1265. 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.
1266. 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.
1267. Supparatpinyo K, Chiewchanvit S, Hirunsri P, et al. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992;75:688-91.
1268. Manosuthi W, Chaovavanich A, Tansuphaswadikul S, et al. Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting. J Infect 2007;55:464-9.
1269. Gupta S, Mathur P, Maskey D, Wig N, Singh S. Immune Restoration Syndrome with disseminated Penicillium marneffei and Cytomegalovirus co-infections in an AIDS patient. AIDS Res Ther 2007;4:21.
1270. Supparatpinyo K, Schlamm HT. Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. Am J Trop Med Hyg 2007;77:350-3.
1271. 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.
1272. Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007;21:365-7.
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