Infection due to Penicillium marneffei (renamed to Talaromyces marneffei in 2011) has emerged as an important public health problem over the past two decades due to the arrival of the HIV epidemic in Asia. Since 2004, P. marneffei has become the second most common pathogen isolated from routine blood culture, after Cryptococcus neoformans, at the Hospital for Tropical Diseases in Ho Chi Minh City, the largest referral centre for HIV care in southern Vietnam. The clinical epidemiology of P. marneffei infection has not been studied in Vietnam. The fundamental epidemiological questions regarding the pathogen reservoirs and risks of acquisition remain poorly understood. The diagnosis relies on isolation of the pathogen from clinical specimens and can take up to 14 days to identify, resulting in delayed initiation of therapy which is associated with worse treatment outcomes. This thesis aims to increase knowledge and understanding of the clinical and environmental epidemiology of P. marneffei infection and to improve the speed and accuracy of diagnosis of P. marneffei infection. The Précis provides a brief background and rationale for the thesis. Chapter 1 is an introductory chapter and provides an overview of the epidemiology, ecology, mycology, pathology, immunology, clinical features, diagnosis, and treatment of P. marneffei infection. Chapter 2 summarizes the incidence and features of P. marneffei admissions at the Hospital for Tropical Diseases in Ho Chi Minh City over a 13 year period. During this period, 795 patients with P. marneffei infection were identified and hospital charts were obtainable for 513 (65%) patients. The data showed clear seasonality with an increase in incidence of approximately 30% during the rainy season compared to the dry season. The clinical and microbiological features and treatment outcomes of the patients were characterised. Poor outcome, defined as death or worsening disease at hospital discharge, occurred in 28% of patients. History of injection drug use, shorter duration of illness, absence of fever or skin lesions, higher respiratory rates, and lower platelet counts independently predicted poor outcome. Chapter 3 describes an analysis of meteorological factors that determine penicilliosis incidence in Ho Chi Minh City. Humidity, rather than precipitation, was the most important factor that governs the seasonality of penicilliosis. Higher humidity was associated with increased odds of penicilliosis versus cryptococcosis admissions. The infection incubation period was estimated to be between one and three weeks. Chapter 4 describes an analysis of exposure and behavioural risk factors for penicilliosis based on a matched case control study of 205 culture-confirmed HIV-infected penicilliosis cases and 405 HIV-infected controls recruited from two major HIV referral centres in Hanoi and Ho Chi Minh City. Penicilliosis was independently associated with proximity or exposure to tropical plants and exposure to farmed animals. The geographical analysis showed that patients living in or traveling to the highland regions were at increased risk for penicilliosis in southern Vietnam. Chapter 5 describes the development of a Taqman real-time PCR assay based on a novel Mp1 gene target unique to P. marneffei for rapid detection of P. marneffei infection in patient plasma. The assay was tested in 70 plasma samples from HIV-infected patients (50 with culture-confirmed penicilliosis, 20 with other opportunistic infections) and showed a clinical specificity of 100% (20/20) and sensitivity of 70.4% (19/27) and 52.2% (12/23) prior to and within 24-48 hours of antifungal therapy administration, respectively. Chapter 6 is an overview discussion interpreting the implications of the major findings and the future direction of P. marneffei research. The work of this thesis increases knowledge of the clinical epidemiology of P. marneffei infection in Vietnam, providing essential data for the design of prospective studies to improve the diagnosis and treatment of P. marneffei infection in Asia. The data suggest that multiple environmental factors including humidity, tropical plants, farmed animals, and highland location, are important drivers of P. marneffei infection in southern Vietnam. The real-time PCR assay showed potential as a rapid ‘rule-in' test for P. marneffei in this pilot study and should be prospectively evaluated in a large cohort to determine if it can improve diagnostic speed and crucially, impact patient outcomes. Prevention, diagnosis and elimination all require further research to reduce the high mortality following clinical disease caused by P. marneffei in Asia.

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