871
Penicillium marneffei Infection in Patients Infected with Human Immunodeficiency Virus Khuanchai Supparatpinyo, Siri Chiewchanvit, Panit Hirunsri, Chantana Uthammachai, Kenrad E. Nelson, and Thira Sirisanthana
From the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; and the Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland
From June 1990 to August 1991, 21 patients infected with the human immunodeficiency virus (HIV) presented with systemic mycosis caused by Penicillium marneffei. Between August 1987 and August 1991, only five patients were observed who had P. marneffei infection but not HIV infection. The clinical presentation included fever, cough, and generalized papular skin lesions. For 11 of these 21 patients, the presumptive diagnosis of P. marneffei infection could be made by microscopic examination of Wright's-stained bone marrow aspirate and/or touch smears of skin specimens obtained by biopsy several days before the results of culture were available Initial clinical response to treatment with either parenteral amphotericin B or oral itraconazole was favorable in most patients. Epidemiological and clinical evidence suggest that this systemic mycosis is caused by an important opportunistic pathogen and that it should be included in the differential diagnosis of AIDS, at least for countries in areas of endemicity, i.e., Southeast Asia and China. Penicillium marneffei is an unusual dimorphic fungus that can cause human infection in both healthy and compromised hosts [1]. This systemic mycosis is endemic to countries of Southeast Asia and the southern part of China [1,2]. Thirty-three cases of P. marneffei infection have been published [1-16]. Only eight cases of P. marneffei infection in patients who are also infected with human immunodeficiency virus (HIV) have been reported in the English-language literature [12-16]. We report 21 patients who were infected with both HIV and P. marneffei and present epidemiological evidence that suggests that HIV infection predisposes the patients to this systemic mycosis. Because of the apparent association between HIV infection and disseminated P. marneffei infection, we suggest that this condition be considered an "AIDS-defining" illness as is now the case for disseminated systemic diseases caused by other fungi in HIV-infected individuals (i.e., Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis).
Materials and Methods Patients. All patients seen at Chiang Mai University Hospital who were infected with HIV and P. marneffei were included in the study. The criteria for the diagnosis of P. marneffei infection were (1) isolation of P. marneffei from blood, bone marrow, or other clinical specimens; and/or (2) identification of yeast cells characteristic of P. marneffei in Received 19 November 1991. Reprints and correspondence: Dr. Thira Sirisanthana, Section of Infectious Disease, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50002, Thailand. Clinical Infectious Diseases 1992;14:871-4 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1404-0009$02.00
Wright's-stained bone marrow aspirate or touch smears of skin specimens obtained by biopsy or in tissue sections stained with Grocott-Gomori methenamine–silver nitrate (GGMS) or periodic acid–Schiff (PAS). The diagnosis of HIV infection was made when HIV antibody was determined to be in the patient's serum by ELISA (Vironostika HIV MIXT, Organon Teknika B.V., Boxtel, Holland) on at least two occasions. The western blot test and enumeration of T lymphocyte subsets were not routinely available at our hospital. Mycologic findings. The isolation of P. marneffei from clinical specimens from all patients was performed by one of the authors (C.U.) and was done by incubating the clinical specimens at 25°C on Sabouraud dextrose agar. The isolate that was visible within 2 or 3 days of incubation was subcultured on brain heart infusion agar and incubated at 37°C. The positive culture for P. marneffei was characterized by a dimorphic fungus that grew as a mold at 25°C and a yeast at 37°C. In its mycelial form, the colony was downy and grayish pink and produced a soluble red pigment that diffused into the medium. The conidiophores consisted of basal stripes bearing terminal verticils of three to five metulae. Some metulae bore four to seven phialides that produced ellipsoidal, smooth-walled conidia in chains. Within 2 or 3 days of incubation at 37°C on brain heart infusion agar, the fungus grew as a yeast, forming white-to-tan, soft or convoluted colonies. Microscopic examination of this growth revealed unicellular, pleomorphic, ellipsoidal-to-rectangular cells (-2 gm X 6 gm) that divided by fission and not by budding. Results
Twenty-one patients were found to be infected with HIV and P. marneffei. Diagnosis for these patients was made dur-
872
Supparatpinyo et al.
ing a relatively short period of 14 months between June 1990 and August 1991. Fifteen patients fulfilled both microbiological and histopathologic criteria for the diagnosis of P. marneffei infection. In the other six patients, the diagnosis was made on the basis of the isolation of P. marneffei from cultures of blood, bone marrow, or other clinical specimens. Five additional cases of P. marneffei infection in which there was no evidence of HIV infection were diagnosed between August 1987 and August 1991. These twenty-six cases were the only cases of P. marneffei infection that have been diagnosed at Chiang Mai University Hospital. Clinical manifestations. All but two patients were men. Ages ranged from 18 to 63 years. All patients denied a history of traveling abroad, homosexual activity, or having received any blood transfusion. All male patients had had frequent heterosexual contact with prostitutes in the past few years. One male patient was an iv drug user, and one female patient was a prostitute. The clinical presentation of patients who were seropositive for HIV and infected with P. marneffei included fever (20 patients), anemia (18), marked weight loss (17), skin lesion (16), cough (11), lymphadenopathy (nine), hepatomegaly (nine), diarrhea (four), palatal papules (three), genital ulcer (two), pharyngeal ulcer (one), and splenomegaly (one). The skin lesions in most patients appeared as a generalized papular rash. The lesions occurred more frequently on the face, pinnae, upper trunk, and arms. In some patients, the papules had central necrotic umbilication, giving an appearance not unlike that of the skin lesions of molluscum contagiosum. Three patients with skin lesions also had papules on the hard palate. Three patients presented with chronic ulcers. Two had genital ulcers, and the third had an ulcer in the pharynx. The ulcers were shallow, well demarcated and had a clean base. Their sizes varied from
Penicillium marneffei Infection in Patients Infected with Human Immunodeficiency Virus Khuanchai Supparatpinyo, Siri Chiewchanvit, Panit Hirunsri, Chantana Uthammachai, Kenrad E. Nelson, and Thira Sirisanthana
From the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; and the Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland
From June 1990 to August 1991, 21 patients infected with the human immunodeficiency virus (HIV) presented with systemic mycosis caused by Penicillium marneffei. Between August 1987 and August 1991, only five patients were observed who had P. marneffei infection but not HIV infection. The clinical presentation included fever, cough, and generalized papular skin lesions. For 11 of these 21 patients, the presumptive diagnosis of P. marneffei infection could be made by microscopic examination of Wright's-stained bone marrow aspirate and/or touch smears of skin specimens obtained by biopsy several days before the results of culture were available Initial clinical response to treatment with either parenteral amphotericin B or oral itraconazole was favorable in most patients. Epidemiological and clinical evidence suggest that this systemic mycosis is caused by an important opportunistic pathogen and that it should be included in the differential diagnosis of AIDS, at least for countries in areas of endemicity, i.e., Southeast Asia and China. Penicillium marneffei is an unusual dimorphic fungus that can cause human infection in both healthy and compromised hosts [1]. This systemic mycosis is endemic to countries of Southeast Asia and the southern part of China [1,2]. Thirty-three cases of P. marneffei infection have been published [1-16]. Only eight cases of P. marneffei infection in patients who are also infected with human immunodeficiency virus (HIV) have been reported in the English-language literature [12-16]. We report 21 patients who were infected with both HIV and P. marneffei and present epidemiological evidence that suggests that HIV infection predisposes the patients to this systemic mycosis. Because of the apparent association between HIV infection and disseminated P. marneffei infection, we suggest that this condition be considered an "AIDS-defining" illness as is now the case for disseminated systemic diseases caused by other fungi in HIV-infected individuals (i.e., Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis).
Materials and Methods Patients. All patients seen at Chiang Mai University Hospital who were infected with HIV and P. marneffei were included in the study. The criteria for the diagnosis of P. marneffei infection were (1) isolation of P. marneffei from blood, bone marrow, or other clinical specimens; and/or (2) identification of yeast cells characteristic of P. marneffei in Received 19 November 1991. Reprints and correspondence: Dr. Thira Sirisanthana, Section of Infectious Disease, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50002, Thailand. Clinical Infectious Diseases 1992;14:871-4 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1404-0009$02.00
Wright's-stained bone marrow aspirate or touch smears of skin specimens obtained by biopsy or in tissue sections stained with Grocott-Gomori methenamine–silver nitrate (GGMS) or periodic acid–Schiff (PAS). The diagnosis of HIV infection was made when HIV antibody was determined to be in the patient's serum by ELISA (Vironostika HIV MIXT, Organon Teknika B.V., Boxtel, Holland) on at least two occasions. The western blot test and enumeration of T lymphocyte subsets were not routinely available at our hospital. Mycologic findings. The isolation of P. marneffei from clinical specimens from all patients was performed by one of the authors (C.U.) and was done by incubating the clinical specimens at 25°C on Sabouraud dextrose agar. The isolate that was visible within 2 or 3 days of incubation was subcultured on brain heart infusion agar and incubated at 37°C. The positive culture for P. marneffei was characterized by a dimorphic fungus that grew as a mold at 25°C and a yeast at 37°C. In its mycelial form, the colony was downy and grayish pink and produced a soluble red pigment that diffused into the medium. The conidiophores consisted of basal stripes bearing terminal verticils of three to five metulae. Some metulae bore four to seven phialides that produced ellipsoidal, smooth-walled conidia in chains. Within 2 or 3 days of incubation at 37°C on brain heart infusion agar, the fungus grew as a yeast, forming white-to-tan, soft or convoluted colonies. Microscopic examination of this growth revealed unicellular, pleomorphic, ellipsoidal-to-rectangular cells (-2 gm X 6 gm) that divided by fission and not by budding. Results
Twenty-one patients were found to be infected with HIV and P. marneffei. Diagnosis for these patients was made dur-
872
Supparatpinyo et al.
ing a relatively short period of 14 months between June 1990 and August 1991. Fifteen patients fulfilled both microbiological and histopathologic criteria for the diagnosis of P. marneffei infection. In the other six patients, the diagnosis was made on the basis of the isolation of P. marneffei from cultures of blood, bone marrow, or other clinical specimens. Five additional cases of P. marneffei infection in which there was no evidence of HIV infection were diagnosed between August 1987 and August 1991. These twenty-six cases were the only cases of P. marneffei infection that have been diagnosed at Chiang Mai University Hospital. Clinical manifestations. All but two patients were men. Ages ranged from 18 to 63 years. All patients denied a history of traveling abroad, homosexual activity, or having received any blood transfusion. All male patients had had frequent heterosexual contact with prostitutes in the past few years. One male patient was an iv drug user, and one female patient was a prostitute. The clinical presentation of patients who were seropositive for HIV and infected with P. marneffei included fever (20 patients), anemia (18), marked weight loss (17), skin lesion (16), cough (11), lymphadenopathy (nine), hepatomegaly (nine), diarrhea (four), palatal papules (three), genital ulcer (two), pharyngeal ulcer (one), and splenomegaly (one). The skin lesions in most patients appeared as a generalized papular rash. The lesions occurred more frequently on the face, pinnae, upper trunk, and arms. In some patients, the papules had central necrotic umbilication, giving an appearance not unlike that of the skin lesions of molluscum contagiosum. Three patients with skin lesions also had papules on the hard palate. Three patients presented with chronic ulcers. Two had genital ulcers, and the third had an ulcer in the pharynx. The ulcers were shallow, well demarcated and had a clean base. Their sizes varied from
