During the previous funding period, we have continued to recruit a cohort of non-HIV cryptococcal diseased individuals. We have thus far recruited 70 patients and have begun immunological and genetic characterizations. A subset of these patients that were not responding to conventional therapy were found to exhibit an overly robust immune response with ventriculitis and cerebral edema which was found to be steroid responsive. Since prolonged steroid therapy can be detrimental, we are also testing the response of steroid sparing agents in controlling these severe infections. In collaboration with Sarah Browne LCID/NIAID/NIH, we have identified 4 patients with C. gattii infection who have high levels of neutralizing anti-GMCSF antibody. In addition, we have set up a collaboration with Dr. Kieren Marr at Johns Hopkins and the US-based mycology Study Group (MSG) to recruit and characterize additional patients. Furthermore, in collaboration with the University of Illinois, a cohort of candidemia patients has been used to identify a key genetic locus associated with poor outcome and have obtained a mouse knockout strain and are conducting backcrossing experiments to more rigorously test and validate the genetic associations found in the clinical outcomes trial. We also completed an epidemiology study of cryptococcosis in the US during a 13 year period, in collaboration with B. Prevots, LCID/NIAID/NIH which identified over 30,000 hospitalizations over the study period with a hospital-associated cost of approximately USD 0.5 billion, suggesting that, despite improvements in therapy and prevention of HIV/AIDS, cryptococcosis remains an important fungal disease in the US with substantial human and economic cost.

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Panackal, Anil A; Williamson, Kim C; van de Beek, Diederik et al. (2016) Fighting the Monster: Applying the Host Damage Framework to Human Central Nervous System Infections. MBio 7:e01906-15
Panackal, Anil A; Marr, Kieren A; Williamson, Peter R (2016) Dexamethasone in Cryptococcal Meningitis. N Engl J Med 375:188
Montezuma-Rusca, Jairo M; Powers, John H; Follmann, Dean et al. (2016) Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence. PLoS One 11:e0159727
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