Cryptococcal meningitis (CM) remains a major cause of HIV-related mortality in Africa. Successful management of Cryptococcus in resource-limited areas is often hindered by unsatisfactory or unavailable antifungal regimens. In these settings, treatment failure and relapse are common. Furthermore, widespread availability of ART has led to changes in the meningitis epidemiology in Africa. Persons with cryptococcal meningitis now have more complex disease presentations, with 40-50% presenting while receiving ART. Large knowledge gaps exist in the diagnosis and management of increasing proportions of complex patients, in particular those developing cryptococcal meningitis shortly after initiating ART, second episodes due to paradoxical immune reconstitution inflammatory syndrome (IRIS) with sterile CSF, or second episodes of culture-positive relapse. This mentored international research project is a prospective cohort study of HIV-infected Africans with Cryptococcus in Uganda. The candidate will determine if persons who develop cryptococcal meningitis while already receiving ART will have worse outcomes compared to ART-nave persons in a resource-limited area. The candidate will evaluate whether differential outcomes based on ART status are dependent on expression of biomarkers in cerebrospinal fluid (CSF). Specifically, the candidate will assess whether persons receiving effective ART will have inflammatory patterns of biomarker expression in CSF. Finally, in cases of recurrent symptomatic meningitis, the candidate will evaluate the role of novel laboratory techniques and biomarkers as more sensitive indicators of infection for rapid differentiation of paradoxical IRIS from culture-positive relapse. Dr. Rhein's long-term career goal is to become an independent translational global health researcher who bridges the gap between basic science and clinical research, moving basic science concepts to clinical application in resource-limited settings. During his training to date, Dr. Rhein has spent 4 years on the ground in Kampala, Uganda working on cryptococcal meningitis research. This K01 award will provide for mentored career development using a combination of coursework to supplement current knowledge gaps and practical mentored-research experience to build a strong foundation of laboratory research skills in HIV immunology and CNS pathogenesis. The award will build upon existing international collaborations and help the candidate develop experience in clinical trial design and implementation in an international setting.

Public Health Relevance

In Sub-Saharan Africa, cryptococcal meningitis is the most common cause of meningitis in adults, and causes ~20% of the AIDS-related attributable mortality. In 2015, cryptococcal meningitis caused 70% of meningitis among hospitalized adults in Kampala, Uganda. With the roll out of HIV antiretroviral therapy, the complexity of these patients with Cryptococcus becomes more challenging, worldwide.

National Institute of Health (NIH)
Fogarty International Center (FIC)
Research Scientist Development Award - Research & Training (K01)
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Study Section
International and Cooperative Projects - 1 Study Section (ICP1)
Program Officer
Sina, Barbara J
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Rhein, Joshua; Hullsiek, Kathy H; Evans, Emily E et al. (2018) Detrimental Outcomes of Unmasking Cryptococcal Meningitis With Recent ART Initiation. Open Forum Infect Dis 5:ofy122
Abassi, Mahsa; Rhein, Joshua; Meya, David B et al. (2018) Cryptococcal Disease in the Era of ""Test and Treat"": Is There Cause for Concern? Open Forum Infect Dis 5:ofx274
Ellis, Jayne; Cresswell, Fiona V; Joshua, Rhein et al. (2018) Cryptococcal Meningitis and Tuberculous Meningitis Co-infection in HIV-Infected Ugandan Adults. Open Forum Infect Dis 5:ofy193
Kwizera, Richard; Akampurira, Andrew; Kandole, Tadeo K et al. (2018) Evaluation of trypan blue stain in the TC20 automated cell counter as a point-of-care for the enumeration of viable cryptococcal cells in cerebrospinal fluid. Med Mycol 56:559-564
Mpoza, Edward; Rhein, Joshua; Abassi, Mahsa (2018) Emerging fluconazole resistance: Implications for the management of cryptococcal meningitis. Med Mycol Case Rep 19:30-32
Lofgren, Sarah; Abassi, Mahsa; Rhein, Joshua et al. (2017) Recent advances in AIDS-related cryptococcal meningitis treatment with an emphasis on resource limited settings. Expert Rev Anti Infect Ther 15:331-340
Flynn, Andrew G; Meya, David B; Hullsiek, Katherine Huppler et al. (2017) Evolving Failures in the Delivery of Human Immunodeficiency Virus Care: Lessons From a Ugandan Meningitis Cohort 2006-2016. Open Forum Infect Dis 4:ofx077
Lofgren, Sarah; Hullsiek, Kathy H; Morawski, Bozena M et al. (2017) Differences in Immunologic Factors Among Patients Presenting with Altered Mental Status During Cryptococcal Meningitis. J Infect Dis 215:693-697
Kwizera, Richard; Akampurira, Andrew; Kandole, Tadeo K et al. (2017) Evaluation of trypan blue stain in a haemocytometer for rapid detection of cerebrospinal fluid sterility in HIV patients with cryptococcal meningitis. BMC Microbiol 17:182
Montgomery, Martha P; Nakasujja, Noeline; Morawski, Bozena M et al. (2017) Neurocognitive function in HIV-infected persons with asymptomatic cryptococcal antigenemia: a comparison of three prospective cohorts. BMC Neurol 17:110

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