HIV Immune Reconstitution Inflammatory Syndrome (IRIS) is a newly recognized complication of anti- retroviral therapy (ART) whereby some persons initiating ART experience paradoxically clinical deterioration due to an exaggerated inflammatory response to occult, latent, or previously treated infections. HIV IRIS has emerged as a frequent complication of ART in Sub-Saharan Africa. As cryptococcal meningitis (CM) is the second most common AIDS-defining illness in sub-Saharan Africa, CM-IRIS is a common problem. CM-IRIS is an ideal disease model for studying the epidemiology and pathogenesis of IRIS because CM IRIS causes a distinct, easily recognized clinical syndrome characterized by a clear phenotype of aseptic meningitis. The characteristics of CM-IRIS can be studied at the site of inflammation by sampling cerebrospinal fluid (CSF) from, the compartment where the inflammation occurs. This project is a prospective cohort study of HIV-infected Ugandans with recent CM monitored on ART. The candidate will determine if persons who develop IRIS have worse outcomes compared to persons who do not develop IRIS in a resource-limited area. The candidate will determine if HIV-infected Ugandan patients who develop CM IRIS express biomarkers in their peripheral blood and CSF that can be used to diagnose IRIS or predict which patients are at risk of IRIS. Dr. Boulware's long term career goal is to become an independent translational researcher who bridges the gap between basic science and clinical research, moving basic science concepts to clinical application. This award will provide for mentored development of laboratory research skills in immunology and functional genomics with application of these skills in an international setting.

Public Health Relevance

In Sub-Saharan Africa, cryptococcal meningitis is the second most common AIDS-defining illness, and causes -30% of the AIDS-related attributable mortality. For those surviving their cryptococcal infection who now have access to ART, IRIS occurs in approximately one in three persons and is frequently fatal (40-66%) in resource-limited regions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI073192-04
Application #
8304329
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Bacon, Melanie C
Project Start
2009-09-16
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$132,624
Indirect Cost
$9,824
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
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
Rajasingham, Radha; Williams, Darlisha; Meya, David B et al. (2014) Nosocomial drug-resistant bacteremia in 2 cohorts with cryptococcal meningitis, Africa. Emerg Infect Dis 20:722-4
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
Boulware, David R; Meya, David B; Muzoora, Conrad et al. (2014) Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 370:2487-98
Bahr, Nathan C; Wallace, James; Frosch, Anne E P et al. (2014) Unmasking Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome due to Granulocyte Colony-Stimulating Factor Use in a Patient with a Poorly Differentiated Germ Cell Neoplasm. Case Rep Oncol 7:1-5
Kabanda, Taseera; Siedner, Mark J; Klausner, Jeffrey D et al. (2014) Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis 58:113-6
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 29:269-79
Robertson, Emma J; Najjuka, Grace; Rolfes, Melissa A et al. (2014) Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis. J Infect Dis 209:74-82
Durski, Kara N; Kuntz, Karen M; Yasukawa, Kosuke et al. (2013) Cost-effective diagnostic checklists for meningitis in resource-limited settings. J Acquir Immune Defic Syndr 63:e101-8
Andrade, Bruno Bezerril; Hullsiek, Katherine Huppler; Boulware, David R et al. (2013) Biomarkers of inflammation and coagulation are associated with mortality and hepatitis flares in persons coinfected with HIV and hepatitis viruses. J Infect Dis 207:1379-88

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