Invasive Penicillium marneffel infection in children without Acquired Immunodeficiency Syndrome (AIDS) - an indicator disease for primary Immunodeficiency

Abstract

OBJECTIVES: Penicillium marneffei infection is indigenous to Southeast Asia. Most cases occurred in individuals with AIDS or secondary immunodeficiency. P. marneffei infection in HIV-negative, otherwise healthy persons is rarely reported. From 1996 – 2009, we diagnosed P. marneffei infection in 6 children. Our aim is to review their clinical and immunological features, and to conduct a systematic literature review on P. marneffei infection in children. METHODS: Case records of our patients with P. marneffei infection were reviewed. A systematic review of the English and Chinese literature (1980 to 2009) from Pubmed, China Journal Net and Taiwan Electronic Periodical Services, using the keyword ‘Penicillium marneffei’ or its Chinese equivalent was performed. Case reports/series on patients <18 years with P. marneffei diagnosed by positive cultures or histology were included, and patients stated to be HIV-positive were excluded. Main Results: Among 392 English and 337 Chinese articles about P. marneffei, 21 cases fit the inclusion criteria. There was a male predominance (n=15). All had disseminated disease, and only 10/21 recovered. Two patients had siblings who died of recurrent infections. One patient had CVID and another had CD4-lymphopenia. Details on immunophenotype in other patients were not mentioned. In our cohort (n=6), all patients were HIV-negative. The age at the time of P. marneffei infection ranged from 22 months-15 years. Presentations included multi-focal lymphadenopathy (n=2), pneumonia (n=1), pneumatoceles (n=2) and multi-organ failure (n=1). None had dermatological manifestations. P. marneffei was isolated from lymph-node biopsy (n=2), bronchoalveolar lavage (n=1), blood (n=1) and marrow culture (n=2). Three patients had positive serology. All patients recovered with antifungal therapy. Five patients had history of recurrent infections, including mucocutaneous candidiasis (n=3), tuberculosis (n=2) and sinopulmonary infections (n=2). One patient had chronic granulomatous disease (CGD) while another had hyper-IgE syndrome. CGD and hyper-IgE syndrome were excluded in the other 4 patients; of note, all of them had hypergammaglobulinemia and low NK-cell count at the time of P. marneffei infection, and two had lymphopenia. The patient with concomitant tuberculosis was found to have impaired IL12 and interferon-gamma production. Further delineation of NK and Th17 immunophenotype and molecular studies is ongoing for these patients. CONCLUSION: P. marneffei infection in HIV-negative children is worth attention by doctors working in Southeast Asia, and immunological evaluation is warranted. Vice versa, P. marneffei should be considered in immunocompromised children presenting with prolonged fever, lymphadenopathy, pneumonia, hepatosplenomegaly or sepsis syndrome. Characterization of innate immunity, NK and Th17 functions in these patients may lead to identification of genetic syndromes predisposing to P. marneffei infection.