Penicillium marneffei (Penicilliosis)

Authors: Yu-Tsung Huang, M.D., Chien-Ching Hung, M.D., Ph.D.

(First Edition 1999, Second Edition 2002): Bertrand Dupont, M.D.

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MICROBIOLOGY

P. marneffei is the only known thermal dimorphic Penicillium species. In vitro at 37°C the yeast form which seems to be an arthroconidia is unicellular, oval or elongated, it does not reproduce by budding as most yeasts but by fission. This typical form is easily seen in histopathological section of biopsies or in smear of bone marrow aspirate: a septum divides the cells in two parts -- their size is 2-3 x 2 µm. The intracellular forms are smaller, resembling Histoplasma capsulatum and the extracelluar forms are larger with a transverse septum. The mycelial phase obtained below 37°C has a bluish gray-green center. In 24 to 48 H a red pigment is produced, it diffuses into all the agar medium in a Petri dish. This Penicillium is biverticillate either symmetric or asymmetric, the conidia are smooth-walled in short chains (9).

EPIDEMIOLOGY

The epidemiology of penicilliosis is still mysterious. The bamboo rats are the only animals known to be naturally infected by this fungus. It is thought that P. marneffei is a natural part of the flora inhabiting vegetation and soil. The fungus is present in internal organs of rats with an infection rate varying with the species. How rats are colonized or infected is still unclear. How human beings get infected is still unresolved. Several studies could not establish exposure to bamboo rats as a risk factor for acquiring penicilliosis, but exposure to soil, especially during the rainy season, could be the critical factor (1, 3, 15). Multilocus genotypes showed that P. marneffei isolates from humans are similar to those from bamboo rats with the former isolates containing more diversified genotypes (2). The portal of entry of infection in man is probably the lung.

Autochthonous cases were reported from Northern Thailand, Vietnam, Laos, Taiwan, Indonesia, South China (Guangxi Province), Hong Kong and Eastern India (state of Manipur) (9, 19). One case was also reported from Ghana (Africa) (13). Imported cases in Europe, the United Sates, Canada, Australia and Japan have been described in immunocompromised patients, mainly with AIDS, with a past history of traveling in Southeast Asia, weeks, months or years earlier (9).

The prevalence and incidence of human penicilliosis marneffei infection correlates with the trends of HIV infection (15). Decreases in the numbers of penicilliosis marneffei have been noted in areas where transmission of HIV has been reduced (25).

CLINICAL MANIFESTATION

The disease affects mostly patients with impaired cellular immunity. Apparently healthy persons can contract the disease. In AIDS it occurs at an advanced stage of HIV disease with a CD4 cell count below 100 cells/mm³. In Northern Thailand, in HIV-infected patients, penicilliosis is the third most common opportunistic infection, accounting for 15 to 20% of all AIDS-related illness, after tuberculosis and cryptococcosis (23). The disease is characterized by fever, weight loss, lung infiltrates, papulonecrotic skin lesions, hepatosplenomegaly, lymphadenopathy, diarrhea and anemia or pancytopenia (7, 10, 15, 25). In HIV-uninfected patients, they were less likely to have fever, splenomegaly, skin lesions and fungemia as compared to HIV-infected patients (14). Osteolytic lesions may present in disseminated penicilliosis marneffei infections; especially in HIV-uninfected patients, and poor prognosis of these patients has been reported (14, 18). Chest X ray or computer tomography may show nodular lesions, reticular infiltration or cavitary lung lesions. Penicilliosis marneffei is a common etiology of cavitary lung lesions in HIV-infected patients in Taiwan (17). Other negative predictors of in-hospital outcome include injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocytes and thrombocytopenia (15). The disease is lethal if left untreated, particularly in disseminated infections and in immunocompromised hosts; and localized infections can resolve spontaneously. Disseminated penicilliosis marneffei is also a severe disease with a high mortality rate in HIV-negative children who have underlying immunodeficiency (16).

LABORATORY DIAGNOSIS

The fungus can be detected by direct examination and/or culture of bone marrow aspirate or skin or lymph node biopsy, bronchoalveolar lavage, peritoneal fluid, pleural fluid, CSF, or blood culture (15, 25). On smear or tissue section, the small non-budding septate yeast are characteristic; in culture, the filamentous phase produces a diffusing red pigment and must be differentiated from other species of "red Penicillium". A specific fluorescent-antibody test and an antigen detection test have been developed but they are not commercially available. The monoclonal antibody used in Platelia Aspergillus galactomannan antigen test (Bio-rad) could cross react with the galactomannan of Penicillium species. Elevated serum O.D. index was noted in HIV-infected patients with penicilliosis marneffei infection (11). Molecular diagnosis including single and nested PCR were sensitive and specific for detecting pure cultures and their clinical application needs further investigation.

SUSCEPTIBILITY IN VITRO AND IN VIVO

In Vitro Studies

Penicillium marneffei is classified as a hazardous microorganism to handle and should be manipulated under a safety cabinet or in a biosafety level 3 laboratory according to national or international regulations.

In vitro testing for susceptibility to antifungal agents is not standardized for dimorphic fungi (EUCAST http://www.eucast.org/ast_of_fungi/methods_of_antifungal_susceptibility_testing/). Although major progress has been made for yeasts, the result of in vitro testing of filamentous or dimorphic fungi is still controversial with respect to reproducibility and relevance to clinical outcome. When tested in broth, rapid production of a red pigment confounds reading results either by the naked eye or by a photometer.

In vitro susceptibility testing showed that itraconazole, voriconazole, ketoconazole miconazole, amphotericin B, terbinafine and 5-flucytosine were active against P. marneffei (28). Fluconazole had higher minimum inhibition concentrations against P. marneffei and was considered to be less active. Synergism was observed in micafungin/itraconazole (65%, 13 out of 20 isolates) and micafungin/amphotericin B (50%, 10 out of 20 isolates) using checkerboard technique (2). However, micafungin did not enhance the activity of fluconazole against P. marneffei and no synergism was noted (2).

In Vivo Studies

Animal studies have shown that in experimentally infected hamsters, nystatin can prolong survival time. Oral itraconazole in immunosuppressed guinea pigs achieved a cure, even at a low dosage (29). In this animal model of infection a good correlation was established between in vitro and in vivo data.

ANTIMICROBIAL THERAPY

Currently, the therapy for invasive infection in HIV-infected patients appears to be intravenous amphotericin B (0.6 mg/kg/day) for 2 weeks followed by oral itraconazole (400 mg/day) for 10 weeks (22). In a retrospective study from southern Vietnam, patients receiving intraconazole or amphotericin B had similar response rate (82% vs. 76%; no statistical significance) (15). Amphotericin B, with or without flucytosine and itraconazole, was effective as well as ketoconazole (9). Voriconazole for 12 weeks could be an effective and well-tolerated alternative agent in HIV-infected patients with disseminated disease (27). Two patients received intravenous voriconazole (6 mg/kg twice on day 1, then 4 mg/kg twice daily) and nine had oral voriconazole (400 mg twice daily on day 1, then 200 mg twice daily). Eight out of nine patients evaluated had favorable outcome (27).

In a double-blind trial, 71 of these successfully treated patients received a maintenance therapy with itraconzole 200 mg/d or placebo. None of the 36 patients assigned to itraconzole relaped. 20 or 35 patients (57%) assigned to placebo had relapsed within one year (26). In HIV-uninfected patients with osteolytic lesions, prolonged antifungal treatment may be necessary (18). In the retrospective study conducted in Guangxi, 12 patients received antifungal therapy. Four patients died during treatment and 4 out of 8 recovered patients suffered disease relapse within 3 - 24 months (18).

PREVENTION

The role of primary prophylaxis using itraconazole (200 mg/day) in HIV-infected patients with CD4⁺count below 150 cells/mm³ had been explored in a randomized placebo-controlled, double-blinded trial (6). Decreased incidence of penicilliosis marneffei was noted but no survival benefit was found in the prophylaxis group. Only a few patients in the study received antiretroviral therapy, however. Further investigation of primary prophylaxis is needed in the ear of highly active antiretroviral therapy (HAART). Long-term secondary prophylaxis with itraconazole (200 mg once daily) was recommended in the pre-HAART era (26). Discontinuation of secondary prophylaxis seems to be safe for HIV-infected patients on HAART with a CD4⁺ count above 100 cells/mm³ for more than 6 months (4, 12). Immune reconstitution inflammatory syndrome from P. marneffei in HIV-infected patients who started HAART is rare and could be managed with timely antifungal treatment (24).

REFERENCES

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