Central nervous system (CNS) infections are common in Sub-Saharan Africa, either with or without HIV-infection across all ages. In persons with HIV, cryptococcal meningitis (CM) is the second most common AIDS defining illness in Africa, and now with the availability of HIV antiretroviral therapy (ART), long term survival should be possible. However, the new challenge of HIV immune reconstitution inflammatory syndrome (IRIS) has emerged. IRIS is a poorly understood immunologic phenomenon whereby a portion of persons (~30%) with AIDS starting ART paradoxically worsen as their immune systems improve. IRIS events are characterized by exaggerated inflammation in the setting of microbiologic treatment success. When the dysregulated inflammation of IRIS occurs in the CNS, death frequently occurs, yet the neurologic outcome among survivors is unknown. We propose a prospective cohort study of persons presenting with CNS infections in Sub- Saharan Africa with HIV-infection. We will use molecular diagnostics to determine the etiologies of CNS infections. After persons initiate ART, we will prospectively conduct surveillance for IRIS and assess neurological, functional, and neuro-cognitive status. We will profile cytokines in the cerebrospinal fluid (CSF) to discover biomarkers predictive of poor neurologic outcome, future IRIS, and/or death. Hypothesis: We hypothesize that persons with advanced HIV (CD4 <100) have worse neurologic outcomes, and persons with subsequent CNS-related IRIS events have worse neurologic outcomes than those who do not experience CNS-IRIS. We hypothesize that pro-inflammatory baseline cytokine profiles of the CNS will be predictive of future adverse outcomes.
Specific Aims 1) We will determine the etiology and neurologic outcomes of CNS infections in Sub-Saharan Africa among adolescents, adults, and elderly with HIV-infection. 2) For AIDS patients who have IRIS-related CNS infections, we will determine their neurologic outcomes after they initiate antiretroviral therapy (ART) in order to determine if patients who develop Immune Reconstitution Inflammatory Syndrome (IRIS) have worse outcomes compared to those who do not develop IRIS. 3) We will determine whether specific CSF cytokine profiles can predict worse neurological outcomes in patients with CNS infections or predict IRIS in patients with CNS infections and AIDS.

Public Health Relevance

Cryptococcal meningitis (CM) is the second most common AIDS defining illness in Sub- Saharan Africa causing 30% of the AIDS-attributable mortality in Africa. Other CNS infections also occur, including aseptic meningitis of unknown etiology. With the availability of antiretroviral therapy (ART), the new challenge of Immune Reconstitution Inflammatory Syndrome (IRIS) occurs resulting in paradoxical clinical deterioration and mortality. The impact of IRIS on neurologic outcomes is unknown. Biomarkers to predict IRIS are needed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS065713-01A1
Application #
7920491
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (51))
Program Officer
Wong, May
Project Start
2010-05-15
Project End
2012-04-30
Budget Start
2010-05-15
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$145,497
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Meya, David B; Okurut, Samuel; Zziwa, Godfrey et al. (2017) Monocyte Phenotype and IFN-?-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome. J Fungi (Basel) 3:
Meya, David B; Manabe, Yukari C; Boulware, David R et al. (2016) The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum. Curr Opin Infect Dis 29:10-22
Boulware, David R; von Hohenberg, Maximilian; Rolfes, Melissa A et al. (2016) Human Immune Response Varies by the Degree of Relative Cryptococcal Antigen Shedding. Open Forum Infect Dis 3:ofv194
Meya, David B; Okurut, Samuel; Zziwa, Godfrey et al. (2015) Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome. J Infect Dis 211:1597-606
Scriven, James E; Rhein, Joshua; Hullsiek, Katherine Huppler et al. (2015) Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis 212:769-78
Rajasingham, Radha; Rhein, Joshua; Klammer, Kate et al. (2015) Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am J Trop Med Hyg 92:274-9
Boulware, David R; Rolfes, Melissa A; Rajasingham, Radha et al. (2014) Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis 20:45-53
Carlson, Renee Donahue; Rolfes, Melissa A; Birkenkamp, Kate E et al. (2014) Predictors of neurocognitive outcomes on antiretroviral therapy after cryptococcal meningitis: a prospective cohort study. Metab Brain Dis 29:269-279
Rolfes, Melissa A; Hullsiek, Kathy Huppler; Rhein, Joshua et al. (2014) The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 59:1607-14
Nabeta, Henry W; Bahr, Nathan C; Rhein, Joshua et al. (2014) Accuracy of noninvasive intraocular pressure or optic nerve sheath diameter measurements for predicting elevated intracranial pressure in cryptococcal meningitis. Open Forum Infect Dis 1:ofu093

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