Penicillium marneffei Infection in HIV-Infected Travelers

Abstract and Commentary

By Patricia Cristofaro, MD, and Maria D. Mileno, MD

Patricia Cristofaro is Assistant Professor, Department of Infectious Diseases, Brown University, and Maria D. Mileno is Director, Travel Medicine, The Miriam Hospital; Associate Professor of Medicine and Infectious Diseases; Director, International Travelers' Clinic, Brown University School of Medicine

Dr. Cristofaro reports no financial relationship relevant to this field of study, and Dr. Mileno is a consultant for GlaxoSmithKline.

This article originally appeared in the October 2006 issue of Travel Medicine Advisor. It was originally edited by Frank Bia, MD, MPH, and peer reviewed by Mary-Louise Scully, MD. Dr. Bia is Professor of Medicine and Laboratory Medicine; Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine, and Dr. Scully works for the Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA. Dr. Bia is a consultant for Pfizer and Sanofi Pasteur, and Dr. Scully reports no financial relationships relevant to this field of study.

Synopsis: Disseminated Penicillium marneffei infection is the third most common AIDS-defining illness in parts of Southeast Asia. A review of the literature now shows that penicilliosis may represent an emergent opportunistic infection in HIV-positive travelers to endemic regions as well.

Source: Antinori S, et al. Disseminated Penicillium marneffei Infection in an HIV-Positive Italian Patient and a Review of Cases Reported Outside Endemic Regions. J Travel Med. 2006;13:181-188.

Antinori and colleagues describe the second case of HIV-associated penicilliosis in Italy caused by P. marneffei (the first was reported by Viviani in 1993),1 and then summarize the epidemiological, microbiological, and clinical characteristics of all cases from non-endemic regions reported in the literature, a total of 35 cases, abstracted from a Medline search covering 1988 to December 2004.2

Case: During an interview with a physician regarding his wife's medical care, a 36-year-old HIV-positive Italian man who had resided in northern Thailand was noted to have several maculopapular lesions on his face reminiscent of mulluscum contagiosum. He reported these lesions had appeared about 8 weeks previously, concurrent with mild fever (37.5° C) and a 6 kg weight loss. Physical exam was unremarkable except for the presence of similar lesions on the trunk and limbs. Diagnostic testing included hematochemical blood studies, chest radiograph, skin biopsy, blood cultures, and bone marrow aspirate. He was started on empiric therapy with itraconazole (600 mg/day orally) because of high clinical suspicion for penicilliosis, given the combination of his HIV status, his residence in the province of Chiang Ray ,Thailand,3 and the character of his rash.

Laboratory examination revealed mild anemia (hemoglobin 11.1 g/dL), CD4 count of 6 cells/µl, and an HIV-RNA viral load of 213,047 copies/mL. Both skin biopsies (H&E, PAS, silver stains) and bone marrow aspirate revealed intra- and extracellular organisms consistent with P. marneffei — round to oval thin-walled yeast-like organisms, some with a central septum. Within 5 days blood, bone marrow, and skin cultures also grew P. marneffei. He was then switched to liposomal amphotericin B (3 mg/kg/d), which he received for 2 weeks, at which time his blood cultures were negative. He was then started on itraconazole (400 mg/day orally) and antiretrovirals (stavudine, lamivudine, efavirenz). At that time, his skin lesions had nearly resolved. He returned to Thailand, where his antifungal maintenance therapy was discontinued when his CD4 count reached 292.

An extensive literature review provided great detail on the epidemiological, microbiological, and clinical characteristics of all cases of penicilliosis in HIV-infected persons from non-endemic regions reported in the literature. A total of 35 cases, abstracted from a Medline search from 1988 to December 2004. Penicilliosis presented late in the course of HIV infection: the median CD4 count was 20 (range, 1-110); 3 patients had a second, concurrent AIDS-defining illness; 12 patients (34%) carried a diagnosis of AIDS. None of the patients were on successful HAART at the time of diagnosis. Twenty-two of the patients were travelers to endemic areas — 8 exclusively to Thailand, 9 to Thailand plus other Asian countries, 5 to other Asian countries including Hong Kong, China, and India.

Clinical characteristics included fever (88.9%), weight loss (66.7%), and skin lesions (52.8%), a triad frequently recognized in disseminated P. marneffei infection.4 Hepatomegaly was present in 36.1%, splenomegaly in 33.3%, and lymphadenopathy in 33.3%. When a CXR was taken, it was abnormal in 51.8%. Diagnosis was made by histology plus culture in 63.9%, culture alone 30.5%, and histology alone 5.5%.

Commentary

HIV-infected travelers, particularly those not taking successful HAART therapy, are at increased risk of acquiring a number of opportunistic infections when traveling. P. marneffei has now emerged as a cause for concern for travel to southeast Asia. Cases have been reported from HIV- infected residents of Thailand, especially Northern Thailand, Myanmar (Burma), Vietnam, Cambodia, Malaysia, Indonesia, northeastern India, Hong Kong, Taiwan, and southern China.3,4 Despite careful case-control studies, the exact source of the infection has not yet been identified, but is suspected to be the inhalation and/or ingestion of infected soil.5 In the article under discussion, Antinori et al describe 35 imported cases occurring over a 16-year period, 22 of which occurred in travelers. This is one of the most comprehensive descriptions of this illness in HIV-infected persons; however, the duration of travel for these patients, and the number of similar travelers exposed but not infected, is unknown. Therefore, it is difficult to predict the risk for any individual prior to departure. However, another recent case report by Carey and colleagues describes an individual with disseminated P. marneffei, CD4 count 3 cells/mL, who had traveled throughout southeast Asia and India for a duration of only 6 weeks — 4 months prior to admission for this illness;6 therefore, prolonged residence does not seem to be required.

Of more practical concern would be the inclusion of penicilliosis in the differential diagnosis of illness in the returning immunocompromised traveler who has visited an endemic area. The most common presentation is the triad of fever, skin lesions and weight loss, often with bone marrow, lymph node, or hepatic involvement. The skin lesions are distributed over the face, ears, limbs, and occasionally genitalia, and may have central umbilication due to necrosis, resembling the lesions of molluscum contagiosum. Hepatic involvement presents with fever, abdominal pain, hepatomegaly, and elevated serum alkaline phosphatase. The diagnosis can be made rapidly by Wright staining of bone marrow aspirate, skin scrapings, or lymph node biopsy, confirmed by culture of blood and appropriate biopsy material, which should become positive after about 5 days incubation.

Consensus guidelines for the treatment of adults and adolescents are now available from a combined committee of the CDC, NIH, and the HIV Medicine Association of the Infectious Disease Society of America.7 The recommended therapy is amphotericin B at a dose of 0.6 mg/kg/day administered IV for 2 weeks, followed by oral itraconazole solution at a dose of 400 mg/day for a duration of 10 weeks. In order to prevent relapse, chronic maintenance therapy of itraconazole 200 mg/day should be administered. Itraconazole should be avoided during the first trimester of pregnancy. There are currently no pediatric guidelines, but both amphotericin B and itraconazole have been successfully used in children for disseminated histoplasmosis.8 HAART should be initiated concurrently, if possible. Some practitioners discontinue secondary prophylaxis after a CD4 count > 200 has been achieved for 6 months. A single report supports this approach, which is largely based on experience with other fungal opportunistic infections.9

References

  1. Viviani MA, et al. Treatment and Serological Studies of an Italian Case of Penicilliosis marneffei Contracted in Thailand by a Drug Addict Infected with the Human Immunodeficiency Virus. Eur J Epidemiol. 1993;9:79-85.
  2. Antinori S, et al. Disseminated Penicillium marneffei Infection in an HIV-Positive Italian Patient and a Review of Cases Reported Outside Endemic Regions. J Travel Med. 2006;13:181-188.
  3. Supparatpinyo K, et al. Disseminated Penicillium marneffei Infection in Southeast Asia. Lancet. 1994;344:110-113.
  4. Sirisanthana T, Supparatpinyo K. Epidemiology and Management of Penicilliosis in Human Immunodeficiency Virus-Infected Patients. Int J Infect Dis. 1998;3:48-53.
  5. Chariyalertsak S, et al. Case-Control Study of Risk Factors for Penicillium marneffei Infection in Human Immunodeficiency Virus-Infected Patients in Northern Thailand. Clin Infect Dis. 1997;24:1080-1086.
  6. Carey J, et al. Penicillium marneffei Infection in an Immunocompromised Traveler: A Case Report and Literature Review. J Travel Med. 2005;12:291-294.
  7. Benson CA, et al. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: Recommendations from the CDC, the NIH, and the HIVMA/IDSA. Clin Infect Dis. 2005;40:S131-S235.
  8. Mofenson LM, et al. Treating Opportunistic Infections Among HIV-Exposed and Infected Children: Recommendations from the CDC, the NIH, and the IDSA. Clin Infect Dis. 2005;40:S1-S84.
  9. Sun HY, et al. Endemic Fungal Infections Caused by Cryptococcus neoformans and Penicillium marneffei in Patients Infected with HIV and Treated with HAART. Clin Microbiol Infect. 2006;12:381-388.